Hdac inhibitors

ABSTRACT

Disclosed herein are compounds of formula (I), and methods of inhibiting histone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3) using compounds of formula (I).

CROSS REFERENCE TO RELATED APPLICATIONS

The benefit of U.S. Provisional Application No. 61/800,170, filed Mar.15, 2013, and U.S. Provisional Application No. 61/863,235, filed Aug. 7,2013, is claimed, the disclosures of which are each incorporated byreference in their entirety.

TECHNICAL FIELD

This disclosure is directed generally to compounds which can inhibithistone deacetylase (“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3).

BACKGROUND

To date, 18 HDACs have been identified in humans and there is increasingevidence that the 18 histone deacetylases (HDAC) in humans are notredundant in function. HDACs are classified into three main groups basedon their homology to yeast proteins. Class I includes HDAC1, HDAC2,HDAC3, and HDAC8 and have homology to yeast RPD3. HDAC4, HDAC5, HDAC7,and HDAC9 belong to class IIa and have homology to yeast HDAC1. HDAC6and HDAC10 contain two catalytic sites and are classified as class IIb,whereas HDAC11 has conserved residues in its catalytic center that areshared by both class I and class II deacetylases and is placed in classIV. These HDACs contain zinc in their catalytic site and are inhibitedby compounds like trichostatin A (TSA) and vorinostat [suberoylanilidehydroxamic acid (SAHA)]. Class III HDACs are known as sirtuins. Theyhave homology to yeast Sir2, require NAD⁺ as cofactor, and do notcontain zinc in the catalytic site. In general, HDAC inhibitors ofzinc-dependent HDACs include a Zn-binding group, as well as a surfacerecognition domain.

HDACs are involved in the regulation of a number of cellular processes.Histone acetyltransferases (HATs) and HDACs acetylate and deacetylatelysine residues on the N termini of histone proteins thereby affectingtranscriptional activity. They have also been shown to regulatepost-translational acetylation of at least 50 non-histone proteins suchas α-tubulin (see for example Kahn, N et al Biochem J 409 (2008) 581,Dokmanovic, M et al Mol Cancer Res 5 (2007) 981).

Altering gene expression through chromatin modification can beaccomplished by inhibiting histone deacetylase (HDAC) enzymes. There isevidence that histone acetylation and deacetylation are mechanisms bywhich transcriptional regulation in a cell—a major event in celldifferentiation, proliferation, and apoptosis—is achieved. It has beenhypothesized that these effects occur through changes in the structureof chromatin by altering the affinity of histone proteins for coiled DNAin the nucleosome. Hypoacetylation of histone proteins is believed toincrease the interaction of the histone with the DNA phosphate backbone.Tighter binding between the histone protein and DNA can render the DNAinaccessible to transcriptional regulatory elements and machinery. HDACshave been shown to catalyze the removal of acetyl groups from theε-amino groups of lysine residues present within the N-terminalextension of core histones, thereby leading to hypoacetylation of thehistones and blocking of the transcriptional machinery and regulatoryelements.

Inhibition of HDAC, therefore can lead to histone deacetylase-mediatedtranscriptional derepression of tumor suppressor genes. For example,cells treated in culture with HDAC inhibitors have shown a consistentinduction of the kinase inhibitor p21, which plays an important role incell cycle arrest. HDAC inhibitors are thought to increase the rate oftranscription of p21 by propagating the hyperacetylated state ofhistones in the region of the p21 gene, thereby making the geneaccessible to transcriptional machinery. Further, non-histone proteinsinvolved in the regulation of cell death and cell-cycle also undergolysine acetylation and deacetylation by HDACs and histone acetyltransferase (HATs).

This evidence supports the use of HDAC inhibitors in treating varioustypes of cancers. For example, vorinostat (suberoylanilide hydroxamicacid (SAHA)) has been approved by the FDA to treat cutaneous T-celllymphoma and is being investigated for the treatment of solid andhematological tumors. Further, other HDAC inhibitors are in developmentfor the treatment of acute myelogenous leukemia, Hodgkin's disease,myelodysplastic syndromes and solid tumor cancers. Selective HDAC 1/2inhibitors may also be useful in treating B-cell acute lymphoblasticleukemia (B-ALL) (Stubbs, et al., Selective Inhibition of HDAC1 andHDAC2 is a Potential Therapeutic Option for B-ALL, MolecularPharmacology, Drug Resistance: Poster II, Poster Board II-780 (Dec. 5,2010) and Witter et al., Bioorg. Med. Chem. Lett., 18:726-731 (2008) andFournel et al., Mol. Cancer Ther. 7(4):759-68 (2008)).

HDAC inhibitors have also been shown to inhibit pro-inflammatorycytokines, such as those involved in autoimmune and inflammatorydisorders (e.g. TNF-α). For example, the HDAC inhibitor MS275 was shownto slow disease progression and joint destruction in collagen-inducedarthritis in rat and mouse models. Other HDAC inhibitors have been shownto have efficacy in treating or ameliorating inflammatory disorders orconditions in in vivo models or tests for disorders such as Crohn'sdisease, colitis, and airway inflammation and hyper-responsiveness. HDACinhibitors have also been shown to ameliorate spinal cord inflammation,demyelination, and neuronal and axonal loss in experimental autoimmuneencephalomyelitis (see for example Wanf L. et al., Nat Rev Drug Disc,8:969 (2009)).

Triplet repeat expansion in genomic DNA is associated with manyneurological conditions (e.g., neurodegenerative and neuromusculardiseases) including myotonic dystrophy, spinal muscular atrophy, fragileX syndrome, Huntington's disease, spinocerebellar ataxias, amyotrophiclateral sclerosis, Kennedy's disease, spinal and bulbar muscularatrophy, Friedreich's ataxia and Alzheimer's disease. Triplet repeatexpansion may cause disease by altering gene expression. For example, inHuntington's disease, spinocerebellar ataxias, fragile X syndrome, andmyotonic dystrophy, expanded repeats lead to gene silencing. InFriedreich's ataxia, the DNA abnormality found in 98% of FRDA patientsis an unstable hyper-expansion of a GAA triplet repeat in the firstintron of the frataxin gene (see Campuzano et al., Science 271:1423(1996)), which leads to frataxin insufficiency resulting in aprogressive spinocerebellar neurodegeneration. Since they can affecttranscription and potentially correct transcriptional dysregulation,HDAC inhibitors have been tested and have been shown to positivelyaffect neurodegenerative diseases (see Herman D et al, Nat Chem Bio 2551 (2006) for Friedreich's ataxia, Thomas E A et al, Proc Natl Acad SciUSA 105 15564 (2008) for Huntington's disease).

HDAC inhibitors may also play a role in cognition-related conditions anddiseases. It has indeed become increasingly evident that transcriptionis likely a key element for long-term memory processes (Alberini C M,Physiol Rev 89 121 (2009)) thus highlighting another role forCNS-penetrant HDAC inhibitors. Although studies have shown thattreatment with non-specific HDAC inhibitors such as sodium butyrate canlead to long-term memory formation (Stefanko D P et al, Proc Natl AcadSci USA 106 9447 (2009)), little is known about the role of specificisoforms. A limited number of studies have shown that, within class IHDACs, main target of sodium butyrate, the prototypical inhibitor usedin cognition studies, HDAC2 (Guan J-S et al, Nature 459 55 (2009)) andHDAC3 (McQuown S C et al, J Neurosci 31 764 (2011)) have been shown toregulate memory processes and as such are interesting targets for memoryenhancement or extinction in memory-affecting conditions such as, butnot limited to, Alzheimer's disease, post-traumatic stress disorder ordrug addiction.

HDAC inhibitors, e.g., HDAC1 and/or HDAC 2 selective inhibitors, mayalso be useful to treat sickle cell disease (SCD) and β-thalassemia(bT). They may also be useful in treating mood disorders or braindisorders with altered chomatin-mediated neuroplasticity (Schoreder, etal., PLoS ONE 8(8): e71323 (2013)).

HDAC inhibitors may also be useful to treat infectious disease such asviral infections. For example, treatment of HIV infected cells with HDACinhibitors and anti-retroviral drugs can eradicate virus from treatedcells (Blazkova j et al J Infect Dis. 2012 Sep. 1; 206(5):765-9; ArchinN M et al Nature 2012 Jul. 25, 487(7408):482-5).

SUMMARY

This disclosure features compounds having formula (I), or apharmaceutically acceptable salt thereof:

compositions (e.g., pharmaceutical compositions) containing the same andmethods of using the same. For purposes of clarification, formula (I)encompasses both formulas (Ia) and (Ib) below:

The formula (I) compounds described herein inhibit histone deacetylase(“HDAC”) enzymes (e.g., HDAC1, HDAC2, and HDAC3). While not wishing tobe bound by theory, it is believed that the ortho-amino (NH₂) benzamideportion of the formula (I) compounds interacts with (e.g., binds to) thezinc in zinc-dependent HDACs.

As the skilled artisan will appreciate, however, cleavage of the amidebond in the formula (I) compounds (e.g., during metabolism of theformula (I) compounds, often studied using in vitro metabolism of theformula (I) compounds in the presence of hepatocytes) can potentiallylead to liberation of o-phenylenediamine (OPD). OPD is an organiccompound having the chemical formula shown below.

OPD is a known animal carcinogen and a suspected human carcinogen. It ismainly used as a chemical intermediate in the synthesis of dyes,pigments and fungicides. OPD is a relatively unstable molecule even inits solid state. OPD can cause acute poisoning in animals leading totremors, convulsions, salivation and respiratory depression [1].Although OPD is recognized as an animal carcinogen, studies to establishits relevance to humans, and effects of single and repeated OPD exposurein humans are inconclusive [2]. Adverse effects of OPD such asgenotoxicity, reproductive toxicity, allergenic reactions andcarcinogenicity are reported in several animal studies [1]. Sontag et al(1981) reported that a 78 week-long oral OPD administration lead tosignificant increase in liver tumors in male rats—5 out of 16 rats werefound to be affected in a group administered with a 16000 mg/kg highdose of OPD, while 5 out of 17 were detected with tumors in a 8000 mg/kglow dose group [3, 4]. An article from NCI, described tumor formation onurinary bladder and fore stomach of both male and female rats, andhepatocellular carcinoma in both sexes of mice after dosing with OPD[5]. It also reports OPD as a definitive carcinogen in Fischer 344 ratsand B6C3FI mice [5].

In contrast, studies by Saruta et al (1962) indicated no tumors wereformed due to subcutaneous administration of OPD to rats. Groups of 5rats were administered with a low dose of 45 mg/kg every second day for11 months and a high dose of 90 mg/kg every second day for 5 months.Tumors were not detected in either of the groups [1, 6]. Nonetheless OPDis classified as a suspected human carcinogen by ACGIH in 1989 [2].

The inventors have found, however, that formula (I) compound metabolitesare substantially free of OPD when formula (I) compounds are subjectedto conditions intended to mimic in vivo metabolism pathways. As usedherein, the term “substantially free of OPD” means that OPD was notdetected by LC-MS/MS after (i) incubating a formula (I) compound withhuman, monkey, dog and rat hepatocytes and (ii) treating the metabolitemilieu with an acidic solution of phenylglyoxal in an organic solvent(this addition leads to quantitative formation of 2-phenylquinoxaline,which can be easily quantified with a low lower limit of quantitation(LLOQ)). See the Examples section.

In some embodiments, the formula (I) compounds described herein exhibitadditional attributes, e.g., valuable to development as pharmaceuticallyuseful compounds by demonstrating relatively reduced plasma-proteinbinding (e.g., less than 99% binding, e.g., from 65% to 95% binding,e.g., from 75% to 95% binding, e.g., 75% binding).

Accordingly, in one aspect, a compound having formula (I), or apharmaceutically acceptable salt thereof, are featured:

in which:

-   R₁—X is attached to only one of the ring nitrogen atoms;    -   X is:    -   (i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;    -   (ii) direct bond; or    -   (iii) C═O, C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k),        NR^(k)—SO₂, C(═O)NR^(k) or    -   NR^(k)—C(═O);    -   wherein:        -   Y is bond, CR^(c)═CR^(d), O, NR^(e), or S(O)_(m);        -   each of A and B is, independently, a bond, O, NR^(f), or            S(O)_(m);        -   a is 1,2, or 3;        -   b is 0, 1, 2, or 3;        -   m is 0, 1, or 2;            -   each occurrence of R^(a) and R^(b) is independently                selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl,                NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6                alkoxy, C1-C6 fluoroalkoxy, and cyano; or            -   one or more of the following can apply with respect to                R^(a) and R^(b):            -   any two R^(a), together with the carbons to which each                is attached, together form C3-C6 cycloalkyl or                heterocyclyl including 3-6 ring atoms, in which one of                the heterocyclyl ring atoms is selected from O,S(O)_(m)                and NR^(g); or            -   one R^(a) and one R^(b), together with the carbons to                which each is attached, form C3-C6 cycloalkyl or                heterocyclyl including 3-6 ring atoms, in which one of                the heterocyclyl ring atoms is selected from O;S(O)m and                NR^(g); or            -   any two R^(b), together with the carbons to which each                is attached, form C3-C6 cycloalkyl or heterocyclyl                including 3-6 ring atoms, in which one of the ring atoms                is selected from O;S(O)m and NR^(g);            -   each of R^(c) and R^(d) is independently selected from                H, F, OH, C1-C6 alkyl, C3-5 cycloalkyl, NH₂, OCO—(C1-C6                alkyl), OCO—(C3-C5 cycloalkyl), C1-C6 alkoxy, C1-C6                fluoroalkoxy, and cyano;            -   or R^(c) and R^(d), together with the carbons to which                each is attached form a C5-C7 cycloalkyl or heterocyclyl                including 3-6 ring atoms, in which from 1-2 of the                heterocyclyl ring atoms are independently selected from                O, S(O)_(m) and NR^(g);            -   each occurrence of R^(e), R^(f), R^(g) and R^(g′) is                independently selected from H, C1-C6 alkyl, —C(═O)H,                —C(═O)R^(h), C(═O)O(C1-C6 alkyl), C(═O)N(R^(i))₂, and                SO₂—R^(h); wherein R^(h) is selected from C1-C6 alkyl,                CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10                aryl), and C6-C10 aryl; and each occurrence of R^(i) is                independently selected from H, C1-C6 alkyl,                CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10                aryl), and C6-C10 aryl;            -   each occurrence of R^(j) is independently selected from                H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6                alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6                fluoroalkoxy, and cyano;            -   or R^(j)—C—R^(j) together form C3-C6 cycloalkyl or                heterocyclyl including 3-6 ring atoms, in which one of                the heterocyclyl ring atoms is selected from O; S(O)m                and NR^(j′);            -   each occurrence of R^(j′) and R^(k) is independently                selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R^(m),                C(═O)O(C1-C6 alkyl), C(═O)N(R^(n))₂, and SO₂—R^(m),                wherein R^(m) is selected from C1-C6 alkyl,                CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10                aryl), and C6-C10 aryl; and each occurrence of R^(n) is                independently selected from H, C1-C6 alkyl,                CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10                aryl), and C6-C10 aryl, and wherein the aryl and                heteroaryl portion in R^(m) and R^(n) can be optionally                substituted with 1-3 independently selected substituents                F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6 cycloalkyl,                C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano;    -   further wherein:        -   (a) when each of A and B is a bond, and b is 0, then X has            the following formula: —Y—[C(R^(a))₂]_(a)—;        -   (b) when b is 0 or 1, then A and B cannot both be            heteroatoms; and        -   (c) when A or B serves as the point of connection of X to            the nitrogen ring atoms, then A or B cannot be a heteroatom;    -   R1 is:    -   (i) monocyclic or bicyclic heteroaryl including from 5-10 ring        atoms, which is optionally substituted with from 1-3 R^(o);        wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(o), and S;    -   (ii) C6-C10 aryl, which is optionally substituted with from 1-3        R^(o); or    -   (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is        optionally substituted with from 1-6 R^(o);    -   (iv) heterocyclyl including from 3-10 ring atoms, which is        optionally substituted with from 1-6 R^(o); wherein from 1-4 of        the ring atoms are a heteroatom independently selected from O,        N, N—H, N—R^(o), and S;    -   (v) hydrogen;    -   R4 is H or R^(o) and each occurrence of R^(o) is independently        selected from the group consisting of halogen; C1-C6 alkyl;        fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;        fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—;        (C1-C6 alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R^(o′)        together form a saturated ring having 5 or 6 ring atoms, in        which 1 or 2 ring atoms are optionally a heteroatom        independently selected from NH, N(C1-C6 alkyl), O, or S; formyl;        formyl(C₁-C₄) alkyl; cyano; cyano(C₁-C₄) alkyl; benzyl;        benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the        heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2        of the ring atoms are a heteroatom independently selected from        NH, N(alkyl), O, or S, and when said alkyl portion is present,        said alkyl portion serves as the point of attachment to R, and        when the alkyl portion is not present, a heterocyclyl carbon        ring atom serves as the point of attachment of the heterocyclyl        to R1; phenyl; heteroaryl including from 5-6 ring atoms, wherein        from 1-4 of the ring atoms are a heteroatom independently        selected from O, N, N—H, N—R^(o″), and S, each of which is        optionally substituted with from 1-3 R^(o″); SO₂—(C1-C6)alkyl;        SO—(C1-C6)alkyl; and nitro;        -   each occurrence of R^(o″) is independently selected from the            group consisting of halogen; C1-C6 alkyl;            fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6            alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6            alkyl)NH—; (C1-C6 alkyl)₂N—; formyl; formyl(C₁-C₄) alkyl;            cyano; cyano(C₁-C₄) alkyl; benzyl; benzyloxy;            (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl            portion includes 5 or 6 ring atoms, in which 1 or 2 of the            ring atoms are a heteroatom independently selected from NH,            N(C1-C6alkyl), O, or S, and when said alkyl portion is            present, said alkyl portion serves as the point of            attachment to R1; and when the alkyl portion is not present,            a heterocyclyl carbon ring atom serves as the point of            attachment of the heterocyclyl to R1; phenyl; heteroaryl            including from 5-6 ring atoms, wherein from 1-4 of the ring            atoms are a heteroatom independently selected from O, N,            N—H, N—(C1-C6 alkyl), and S; SO₂—(C1-C6)alkyl;            SO—(C1-C6)alkyl; and nitro;    -   R5 is selected from the group consisting of: hydrogen, halogen;        C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl;        (C1-C6 alkyl)C(O)—; formyl; formyl(C₁-C₄) alkyl; cyano;        cyano(C₁-C₄) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, wherein        the heterocyclyl portion includes 5 or 6 ring atoms, in which 1        or 2 of the ring atoms are a heteroatom independently selected        from NH, N(C1-C6alkyl), O, or S, and when said alkyl portion is        present, said alkyl portion serves as the point of attachment to        R1; and when the alkyl portion is not present, a heterocyclyl        carbon ring atom serves as the point of attachment of the        heterocyclyl to R1; phenyl; heteroaryl including from 5-6 ring        atoms, wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(q″), and S, each of        which is optionally substituted with from 1-3 R^(q″);        SO₂—(C1-C6)alkyl; SO—(C1-C6)alkyl; and nitro;    -   R2 is selected from H, F, Cl, CF₃, CF₂CF₃, CH₂CF₃, OCF₃, OCHF₂,        phenyl; or phenyl substituted with 1-3 R^(o); and    -   R3 is H, F, or Cl.

In another aspect, a compound of the formula (Ia) is featured.

In another aspect, a compound of the formula (Ib) is featured.

In a further aspect, the formula (I) compounds specifically describedherein (or a salt, e.g., a pharmaceutically acceptable salt thereof) arefeatured (e.g., compounds A1-A24, or A1-A15, e.g., A1, A2, A3, A4, A5,A6, A7, A11, A12, A13, A14, A15, A16, A17, A18, A19, A20, A21, A22, A23,or A24).

In one aspect, a composition (e.g., a pharmaceutical composition) isfeatured, which includes a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein anda pharmaceutically acceptable carrier. In some embodiments, thecomposition can include an effective amount of the compound or itspharmaceutically acceptable salt. In some embodiments, the compositioncan further include an additional therapeutic agent.

In another aspect, a dosage form is featured, which includes from about0.05 milligrams to about 2,000 milligrams (e.g., from about 0.1milligrams to about 1,000 milligrams, from about 0.1 milligrams to about500 milligrams, from about 0.1 milligrams to about 250 milligrams, fromabout 0.1 milligrams to about 100 milligrams, from about 0.1 milligramsto about 50 milligrams, or from about 0.1 milligrams to about 25milligrams) of a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein.The dosage form can further include a pharmaceutically acceptablecarrier and/or an additional therapeutic agent.

Provided herein are methods for inhibiting one (or more) HDACs (e.g.,HDAC1 or HDAC2; e.g., HDAC3) or more than one HDAC (e.g., HDAC1 andHDAC2; e.g., HDAC1 and HDAC3; e.g., HDAC2 or HDAC3; e.g., HDAC1, HDAC2,and HDAC3) with a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein. Insome embodiments, the methods can include, e.g., contacting one (ormore) HDACs (e.g., HDAC1 or HDAC2; e.g., HDAC3) in a sample (e.g., acell or tissue) with a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein. Inother embodiments, the methods can include administering a compound offormula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereofas defined anywhere herein to a subject (e.g., a mammal, such as ahuman). Accordingly, in yet another aspect, provided are methods ofscreening for compounds that inhibit (e.g., selectively inhibit) one ormore HDACs (e.g., HDAC1 or HDAC2; e.g., HDAC3, e.g., HDAC1 and HDAC2;e.g., HDAC1 and HDAC3; e.g., HDAC2 or HDAC3; e.g., HDAC1, HDAC2, andHDAC3).

In one aspect, a method of selectively inhibiting HDAC3 is featured,which includes contacting an HDAC3 in a sample (e.g., a cell or tissue)with a compound of formula (I) or a salt (e.g., a pharmaceuticallyacceptable salt) thereof as defined anywhere herein; or administering acompound of formula (I) or a salt (e.g., a pharmaceutically acceptablesalt) thereof as defined anywhere herein to a subject (e.g., a mammal,such as a human).

In one aspect, a method of selectively inhibiting HDAC1 or HDAC2 (e.g.,HDAC1) is featured, which includes contacting HDAC1 or HDAC2 (e.g.,HDAC1) in a sample (e.g., a cell or tissue) with a compound of formula(I) or a salt (e.g., a pharmaceutically acceptable salt) thereof asdefined anywhere herein; or administering a compound of formula (I) or asalt (e.g., a pharmaceutically acceptable salt) thereof as definedanywhere herein to a subject (e.g., a mammal, such as a human).

In one aspect, a method of selectively inhibiting HDAC1, HDAC2, andHDAC3 is featured, which includes contacting HDAC1, HDAC2, and HDAC3 inone or more samples (e.g., a cell or tissue) with a compound of formula(I) or a salt (e.g., a pharmaceutically acceptable salt) thereof asdefined anywhere herein; or administering a compound of formula (I) or asalt (e.g., a pharmaceutically acceptable salt) thereof as definedanywhere herein to a subject (e.g., a mammal, such as a human).

In one aspect, methods of treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) a disease or disorder mediated by HDAC1 or HDAC2 in asubject (e.g., a mammal, such as a human) in need thereof are featured,which include administering a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein tothe subject.

In one aspect, methods of treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) a disease or disorder mediated by HDAC3 in a subject (e.g.,a mammal, such as a human) in need thereof are featured, which includeadministering a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein tothe subject.

In one aspect, methods of treating (e.g., controlling, relieving,ameliorating, alleviating, or slowing the progression of) or methods forpreventing (e.g., delaying the onset of or reducing the risk ofdeveloping) a disease or disorder mediated by two or more HDACs (e.g.,HDAC1 and HDAC2; e.g., HDAC1 and HDAC3; e.g., HDAC2 or HDAC3; e.g.,HDAC1, HDAC2, and HDAC 3) in a subject (e.g., a mammal, such as a human)in need thereof are featured, which include administering a compound offormula (I) or a salt (e.g., a pharmaceutically acceptable salt) thereofas defined anywhere herein to the subject.

In one aspect, featured are methods of treating (e.g., controlling,relieving, ameliorating, alleviating, or slowing the progression of) ormethods for preventing (e.g., delaying the onset of or reducing the riskof developing) a neurological disorder such as Friedreich's ataxia,myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,Huntington's disease, spinocerebellar ataxia, Kennedy's disease,amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, andAlzheimer's disease; a cancer (e.g. cutaneous T cell lymphoma, B celllymphomas, and colorectal cancer, and B-cell acute lymphoblasticleukemia); an inflammatory disease (e.g.,psoriasis, rheumatoidarthritis, and osteoarthritis); a memory impairment condition; mooddisorder, brain disorder associated with chromatin-mediatedneuroplasticity, post-traumatic stress disorder; a drug addiction;sickle cell anemia, β-thalassemia (bT), a Plasmodium falciparuminfection (e.g., malaria) as well as other parasite infections in asubject (e.g., a mammal, such as a human) in need thereof, which includeadministering a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein tothe subject.

In one aspect, a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein foruse in medicine is featured.

In one aspect, featured is a compound of formula (I) or a salt (e.g., apharmaceutically acceptable salt) thereof as defined anywhere herein forthe treatment of: a disease or disorder mediated by HDAC1 or HDAC2; adisease or disorder mediated by HDAC3; a disease or disorder mediated byHDAC3 and HDAC1 or HDAC2; a disease or disorder mediated by HDAC1 andHDAC2 and HDAC3; a neurological disorder such as Friedreich's ataxia,myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,Huntington's disease, spinocerebellar ataxia, Kennedy's disease,amyotrophic lateral sclerosis, Niemann Pick disease, Pitt Hopkinsdisease, spinal and bulbar muscular atrophy, and Alzheimer's disease; acancer (e.g. cutaneous T cell lymphoma, B cell lymphomas, and colorectalcancer); an inflammatory disease (e.g., psoriasis, rheumatoid arthritis,and osteoarthritis); a memory impairment condition; post-traumaticstress disorder; a drug addiction; an infectious disease such as HIV; aPlasmodium falciparum infection (e.g., malaria) as well as otherparasite infections, B-ALL, bT, sickle cell anemia, mood disorders, orbrain disorders associated with chromatin-mediated neuroplasticity.

In one aspect, featured is a use of a compound of formula (I) or a salt(e.g., a pharmaceutically acceptable salt) thereof as defined anywhereherein, in the preparation of a medicament for the treatment of: adisease or disorder mediated by HDAC1 or HDAC2; a disease or disordermediated by HDAC3; a disease or disorder mediated by HDAC3 and HDAC1 orHDAC2; a disease or disorder mediated by HDAC1 and HDAC2 and HDAC3; aneurological disorder such as Friedreich's ataxia, myotonic dystrophy,spinal muscular atrophy, fragile X syndrome, Huntington's disease,spinocerebellar ataxia, Kennedy's disease, amyotrophic lateralsclerosis, Niemann Pick, Pitt Hopkins disease, spinal and bulbarmuscular atrophy, and Alzheimer's disease; a cancer (e.g. cutaneous Tcell lymphoma, B cell lymphomas, B-ALL, and colorectal cancer); aninflammatory disease (e.g., psoriasis, rheumatoid arthritis, andosteoarthritis); a memory impairment condition; mood disorder, braindisorders with altered chomatin-mediated neuroplasticity, sickle cellanemia, β-thalassemia, post-traumatic stress disorder; a drug addiction;an infectious disease such as HIV; a Plasmodium falciparum infection(e.g., malaria) as well as other parasite infections.

In some embodiments, the subject can be a subject in need thereof (e.g.,a subject identified as being in need of such treatment, such as asubject having, or at risk of having, one or more of the diseases orconditions described herein). Identifying a subject in need of suchtreatment can be in the judgment of a subject or a health careprofessional and can be subjective (e.g. opinion) or objective (e.g.measurable by a test or diagnostic method). In some embodiments, thesubject can be a mammal. In certain embodiments, the subject can be ahuman.

In one aspect, methods of making compounds described herein arefeatured. In embodiments, the methods include taking any one of theintermediate compounds described herein and reacting it with one or morechemical reagents in one or more steps to produce a compound of formula(I) or a salt (e.g., a pharmaceutically acceptable salt) thereof asdefined anywhere herein.

Some of the formula (I) compounds described herein have enhanced (e.g.,increased, e.g., increased by a factor of about 2 or more, e.g.,compared to other o-aminoanilide HDAC inhibitors) stabilities in acid.In some embodiments, the formula (I) compounds have enhanced resistancesto degradation, e.g., less than about 25% degradation (e.g., less thanabout 20% degradation, less than about 15% degradation, or less thanabout 10% degradation) when exposed to acidic pH, e.g., acidicconditions intended to mimic those in the stomach, e.g., incubation(e.g., as a10 μM solution) at 50° C. and at a pH of about 2.0 for aboutfour hours. The resistance of compounds to degradation or metabolism atacidic pH can be a useful feature for a pharmaceutical agent (e.g., adrug). Increased stability at low pH can allow, for example, processpreparation steps, such as salt formation, to occur without significantdegradation of the desired salt. In addition, it is preferable thatorally administered pharmaceuticals are stable to the acidic pH of thestomach. In some embodiments, compounds display enhanced stability whenexposed to acidic pH with stability half-lives greater than e.g. 12 h ore.g. 18 h or e.g. 24 h at pH 2 and 50° C.

In some embodiments, the formula (I) compounds described hereinselectively inhibit HDAC3, e.g., selectively inhibit HDAC3 over HDAC1and HDAC2 (e.g. exhibiting 5-fold or greater selectivity, e.g.exhibiting 25-fold or greater selectivity). While not wishing to bebound by theory, it is believed that HDAC3-selective inhibitors canincrease expression of frataxin, and could therefore be useful in thetreatment of neurological conditions (e.g., neurological conditionsassociated with reduced frataxin expression, such as Friedreich'sataxia). It is also believed that HDAC3 inhibition plays an importantrole in memory consolidation (McQuown S C et al., J Neurosci, 31:764(2011)). Selective inhibitors of HDAC3 could provide advantages fortreatment of neurological conditions over the use of broad-spectrum HDACinhibitors by reducing toxicities associated with inhibition of otherHDACs. Such specific HDAC3 inhibitors would provide a higher therapeuticindex, resulting in better tolerance by patients during chronic orlong-term treatment.

In some further embodiments, compounds selectively inhibit HDAC 1 and/orHDAC2 (e.g., exhibiting 5-fold or greater selectivity, e.g. exhibiting25-fold or greater selectivity).

In some embodiments, the formula (I) compounds described herein inhibitHDAC1, HDAC2, and HDAC3. While not wishing to be bound by theory, it isbelieved that HDAC3-selective inhibitors can increase expression offrataxin, and could therefore be useful in the treatment of neurologicalconditions (e.g., neurological conditions associated with reducedfrataxin expression, such as Friedreich's ataxia).

In some embodiments, the formula (I) compounds described herein havebeen shown to inhibit class I histone deacetylases and this inhibitionhas resulted in an in vitro increased frataxin mRNA expression inFriedreich's ataxia patient peripheral blood mononuclear cells (PBMCs)and in neurons derived from induced pluripotent stem cells generatedfrom Friedreich's ataxia patient cell line.

In some aspects, compounds disclosed herein inhibit in vitroproliferation of colorectal cancer cells in a dose-dependent fashion. Infurther embodiments, compounds disclosed herein which are specific forHDAC3 inhibition and show distribution to the CNS are expected toincrease long term memory in vivo using the novel object recognitionparadigm.

In some embodiments, the formula (I) compounds described herein exhibitenhanced brain penetration. For example, brain/plasma ratios of greaterthan about 0.25 (e.g., greater than about 0.50, greater than about 1.0,greater than about 1.5, or greater than about 2.0) are observed whenmice are dosed with some of the formula (I) compounds described herein.Such compounds are therefore expected to be particularly suitable fortherapies targeting the brain (e.g., neurological conditions such asFriedreich's ataxia, myotonic dystrophy, spinal muscular atrophy,fragile X syndrome, Huntington's disease, Niemann Pick, Pitt Hopkins,spinocerebellar ataxia, Kennedy's disease, amyotrophic lateralsclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease;a memory impairment condition; post-traumatic stress disorder; a drugaddiction).

In some embodiments, the formula (I) compounds described hereinselectively inhibit HDAC3, e.g., selectively inhibit HDAC3 over HDAC1and HDAC2 (e.g exhibiting 5-fold or greater selectivity, e.g. exhibiting25-fold or greater selectivity) and exhibit enhanced brain penetration(e.g., as described above).

In some embodiments, the formula (I) compounds described hereinselectively inhibit HDAC1 and/or HDAC2, e.g., selectively inhibit HDAC1and/or HDAC2 over HDAC3 (e.g exhibiting 5-fold or greater selectivity,e.g. exhibiting 25-fold or greater selectivity) and exhibit enhancedbrain penetration (e.g., as described above).

Embodiments can also include any one or more of the features describedin the detailed description and in the claims.

Definitions

The term “hepatocyte” refers to preparations, e.g., commerciallyavailable preparations, of liver tissue derived cells that can beobtained from mouse, rat, dog, monkey, or human liver tissue.

The term “mammal” includes organisms, which include mice, rats, cows,sheep, pigs, rabbits, goats, horses, monkeys, dogs, cats, and humans.

“An effective amount” refers to an amount of a compound that confers atherapeutic effect (e.g., treats, e.g., controls, relieves, ameliorates,alleviates, or slows the progression of; or prevents, e.g., delays theonset of or reduces the risk of developing, a disease, disorder, orcondition or symptoms thereof) on the treated subject. The therapeuticeffect may be objective (i.e., measurable by some test or marker) orsubjective (i.e., subject gives an indication of or feels an effect). Aneffective amount of the compound described above may range from about0.01 mg/kg to about 1000 mg/kg, (e.g., from about 0.1 mg/kg to about 100mg/kg, from about 1 mg/kg to about 100 mg/kg). Effective doses will alsovary depending on route of administration, as well as the possibility ofco-usage with other agents.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

In general, and unless otherwise indicated, substituent (radical) prefixnames are derived from the parent hydride by either (i) replacing the“ane” in the parent hydride with the suffix “yl;” or (ii) replacing the“e” in the parent hydride with the suffix “yl;” (here the atom(s) withthe free valence, when specified, is (are) given numbers as low as isconsistent with any established numbering of the parent hydride).Accepted contracted names, e.g., furyl, pyridyl, and piperidyl, andtrivial names, e.g., phenyl and thienyl are also used herein throughout.Conventional numbering/lettering systems are also adhered to forsubstituent numbering.

The following definitions are used, unless otherwise described. Specificand general values listed below for radicals, substituents, and ranges,are for illustration only; they do not exclude other defined values orother values within defined ranges for the radicals and substituents.Alkyl, alkoxy, and the like denote both straight and branched groups.

As used herein, the term “alkyl,” employed alone or in combination withother terms, refers to a saturated hydrocarbon group that may bestraight-chain or branched. In some embodiments, the alkyl groupcontains 1 to 12, 1 to 8, or 1 to 6 carbon atoms. Examples of alkylmoieties include, but are not limited to, chemical groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl,sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl,n-hexyl, 1,2,2-trimethylpropyl, n-heptyl, n-octyl, and the like. In someembodiments, the alkyl moiety is methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,or 2,4,4-trimethylpentyl.

Throughout the definitions, the term “Cy-Cz” (e.g., C1-C6 and the like)is used, wherein y and z are integers and indicate the number ofcarbons, wherein y-z indicates a range which includes the endpoints.

As referred to herein, the term “alkoxy group” refers to a group offormula —O(alkyl). Alkoxy can be, for example, methoxy, ethoxy, propoxy,isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 2-pentoxy,3-pentoxy, or hexyloxy.

As used herein, the term “aryl,” employed alone or in combination withother terms, refers to a monocyclic aromatic hydrocarbon moiety or apolycyclic hydrocarbon moiety (e.g., having 2, 3 or 4 fused linkedrings) that includes at least one aromatic ring. Examples include, butare not limited to, phenyl, 1-naphthyl, 2-naphthyl, indanyl andtetralinyl. In some embodiments, aryl groups have from 6 to 10 carbonatoms.

As referred to herein, “heteroaryl” refers to an aromatic monocyclic orfused bicyclic, or polycyclic ring comprising 5-10 ring atoms thatincludes at least one aromatic ring, each of which containing at leastone (typically one to about three) independently selected nitrogen,oxygen, or sulfur ring atoms (independently selected when more than onering is present). Examples of heteroaryl groups include, but are notlimited to pyridyl, pyrazolyl, pyrrolyl, 2-oxo-indolyl, quinolinyl,isoquinolinyl, tetrahydro-isoquinolinyl, benzofuranyl, indolyl,benzodioxanyl, benzodioxolyl (aka. methylenedioxyphenyl) andcorresponding difluoro (CF₂) analog, thiazolyl, 2-oxopyridinyl,pyridinyl N-oxide, pyrimidinyl, thienyl, furanyl, oxazolyl, isoxazolyl,pyridazinyl, imidazolyl, pyrazinyl, isothiazolyl,1,2-thiazinyl-1,1-dioxide, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzotriazolyl, benzoxazolyl, benzothienyl, oxadiazolyl,triazolyl, tetrazolyl, dioxoindolyl (isatin), phthalimido; heteroarylsthat contain a bridgehead nitrogen ring atom and optionally otherheteroatom ring atoms, such as indolizinyl, pyrrolopyrimidinyl,pyrazolopyridinyl, imidazopyridinyl, imidazopyriazinyl,triazolopyridinyl, imidazothiazolyl, imidazooxazolyl); and the dihydroand tetrahydro congeners of the fully unsaturated ring systems.

As used herein, the phrase “optionally substituted” means unsubstituted(e.g., substituted with a H) or substituted. As used herein, the term“substituted” means that a hydrogen atom is removed and replaced by asubstituent. It is understood that substitution at a given atom islimited by valency. The use of a substituent (radical) prefix name suchas alkyl without the modifier “optionally substituted” or “substituted”is understood to mean that the particular substituent is unsubstituted.However, the use of “fluoro Cy-Cz alkyl” without the modifier“optionally substituted” or “substituted” is still understood to mean analkyl group, in which at least one hydrogen atom is replaced by fluoro.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. In generally, the point of attachmentfor a substituent is indicated by the last term in the group. Forexample, (heterocyclyl)-(C1-C6) alkyl refers to a moiety of heterocyclyl-alkylene-, wherein the alkylene linker has 1 to 6 carbons, and thesubstituent is attached through the alkylene linker.

As used herein, the term “cycloalkyl,” employed alone or in combinationwith other terms, refers to a saturated, cyclic hydrocarbon moietycomprising 3-10 carbon atoms. Exemplary cycloalkyl groups include,without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,and cycloheptyl. It is understood that when two substituents are joinedto form a cycloalkyl group, it may be a cycloalkylene.

As used herein, the term “cycloalkenyl,” employed alone or incombination with other terms, refers to a partially saturated, cyclichydrocarbon moiety comprising 3-10 carbon atoms. An exemplarycycloalkenyl group is cyclohexenyl. It is understood that when twosubstituents are joined to form a cycloalkenyl group, it may be acycloalkenylene.

As used herein, the term “cyano,” employed alone or in combination withother terms, refers to a group of formula —CN, wherein the carbon andnitrogen atoms are bound together by a triple bond.

As used herein, the term “halo Cy-Cz alkyl” and the like employed aloneor in combination with other terms, refers to an alkyl group having fromone halogen atom to 2n+1 halogen atoms which may be the same ordifferent, where “n” is the number of carbon atoms in the alkyl group.In some embodiments, the halogen atoms are fluoro atoms.

As used herein, “haloalkoxy,” employed alone or in combination withother terms, refers to a group of formula —O-haloalkyl. An examplehaloalkoxy group is OCF₃. In some embodiments, the halogen atoms arefluoro atoms.

As used herein, the term “heterocyclyl” employed alone or in combinationwith other terms, refers to a saturated ring system comprising 3-10 ringatoms, which has carbon ring atoms and at least one heteroatom ring atomselected from nitrogen, sulfur, and oxygen (independently selected whenmore than one is present). When the heterocyclyl group contains morethan one heteroatom, the heteroatoms may be the same or different.Heterocyclyl groups can include mono- or bicyclic or polycyclic (e.g.,having 2 fused rings) ring systems. Heterocyclyl groups can also includebridgehead heterocycloalkyl groups. As used herein, “bridgeheadheterocyclyl group” refers to a heterocyclyl moiety containing at leastone bridgehead heteroatom (e.g., nitrogen). In some embodiments, thecarbon atoms or hetereoatoms in the ring(s) of the heterocycloalkylgroup can be oxidized to form a carbonyl, or sulfonyl group (or otheroxidized linkage) or a nitrogen atom can be quaternized. It isunderstood that when two substituents are joined to form aheterocycloalkyl group, it may be a heterocycloalkylene.

As to any of the above groups that contain one or more substituents, itis understood, of course, that such groups do not contain anysubstitution or substitution patterns that are sterically impracticaland/or synthetically unfeasible. In addition, the compounds describedherein include all stereochemical isomers arising from the substitutionof these compounds.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art. Although methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsdescribed herein, suitable methods and materials are described below.All publications, patent applications, patents, and other referencesmentioned herein are incorporated by reference in their entirety. Incase of conflict, the present specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and not intended to be limiting.

Other features and advantages of the disclosure will be apparent fromthe following detailed description, and from the claims.

It is appreciated that certain features of the disclosure, which are,for clarity, described in the context of separate embodiments, can alsobe provided in combination in a single embodiment. Conversely, variousfeatures of the disclosure which are, for brevity, described in thecontext of a single embodiment, can also be provided separately or inany suitable sub-combination.

Thus, for ease of exposition, it is also understood that where in thisspecification, a group is defined by “as defined anywhere herein” (orthe like), the definitions for that particular group include the firstoccurring and broadest generic definition as well as any sub-generic andspecific definitions delineated anywhere in this specification. Also,for ease of exposition, the definition “substituent other than hydrogen”refers collectively to the non-hydrogen possibilities for thatparticular variable.

DETAILED DESCRIPTION

This disclosure features compounds having formula (I), or apharmaceutically acceptable salt thereof:

compositions (e.g., pharmaceutical compositions) containing the same andmethods of using the same.

I. COMPOUNDS

A. Variable X

1.

In some embodiments, X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—.Embodiments can also include one or more of the features described in[a]-[d] below.

a.

A is a bond and/or B is a bond (in some embodiments, each of A and B isa bond; or one of A and B (e.g., B) is a bond, and the other of A and B(e.g., A) is other than a bond, e.g., 0 or NR^(f), e.g., O; inembodiments, each of A and B is other than S(O)_(m)).

Each occurrence of R^(a) and R^(b) (when present) is independentlyselected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy C1-C6 fluoroalkoxy, andcyano.

Each occurrence of R^(a) and R^(b) (when present) is independentlyselected from H, F, C1-C6 alkyl, and C3-C6 cycloalkyl.

Each occurrence of R^(a) and R^(b) (when present) is H.

One or more (e.g., one) of the following apply:

any two R^(a), together with the carbons to which each is attached,together form C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms,in which one of the heterocyclyl ring atoms is selected from O; S(O)_(m)and NR^(g); in these embodiments, any remaining occurrences of R^(a) andany occurrence of R^(b) are each independently defined according to anyone or more of the preceding or following definitions pertaining toR^(a) and R^(b); or

one R^(a) and one R^(b), together with the carbons to which each isattached, form C3-C6 cycloalkyl or heterocyclyl including 3-6 ringatoms, in which one of the heterocyclyl ring atoms is selected from O;S(O)_(m) and NR^(g); in these embodiments, the other R^(a), the otherR^(b), and any other remaining occurrences of R^(a) and R^(b) are eachindependently defined according to any one or more of the preceding orfollowing definitions pertaining to R^(a) and R^(b); or

any two R^(b), together with the carbons to which each is attached, formC3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which oneof the ring atoms is selected from O; S(O)_(m) and NR^(g); in theseembodiments, each occurrence of R^(a) and any other remainingoccurrences of R^(b) are each independently defined according to any oneor more of the preceding definitions pertaining to R^(a) and R^(b).

b.

In some embodiments, Y is CR^(c)═CR^(d) (in some embodiments, the doublebond between CR^(c) and CR^(d) has the trans configuration; in otherembodiments, the double bond between CR^(c) and CR^(d) has the cisconfiguration). Embodiments can include one or more of the followingfeatures.

The double bond between CR^(c) and CR^(d) has the trans configuration.Each of R^(c) and R^(d) is, independently, selected from H, F, OH, C1-C6alkyl, C3-C5 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C5 cycloalkyl),C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano. In certain embodiments,each of R^(c) and R^(d) is H.

A is a bond and/or B is a bond (in some embodiments, each of A and B isa bond).

Each of R^(a) and R^(b) can be as defined anywhere herein (see, forexample, the R^(a) and R^(b) features described above in section[I][A][1][a]).

a is 1 or 2 (e.g., 1). b is 0 or 1 (e.g., 0).

a is 1 or 2, e.g., 1; and b is 0 or 1, e.g., 0 (in further embodiments,each of A and B is also a bond.

b is 0 (in embodiments, a is 1 or 2, e.g., 1; in further embodiments,each of A and B is also a bond).

X is —CH═CH—C(R^(a))₂—. In certain embodiments, each R^(a) is hydrogen.In other embodiments, each R^(a) is a substituent other than hydrogen(e.g., C1-C6 alkyl), and each R^(a) can be the same or different, e.g.,the same. For example, each R^(a) can be the same C1-C6 alkyl, such asCH₃.

X is —CH═CH—CH(R^(a))—. In certain embodiments, R^(a) is hydrogen; inother embodiments, R^(a) is a substituent other than hydrogen (e.g., asdescribed above).

X is —CH═CH—C(R^(a))₂—C(R^(a))₂. In certain embodiments, each R^(a) ishydrogen. In other embodiments, each R^(a) is a substituent other thanhydrogen (e.g., C1-C6 alkyl), and each R^(a) can be the same ordifferent, e.g., the same. For example, each R^(a) can be the same C1-C6alkyl, such as CH₃. In still other embodiments, in one germinal pair ofR^(a′)s, each R^(a) is hydrogen; and in the other germinal pair ofR^(a′)s, each R^(a) is a substituent other than hydrogen (e.g., asdescribed above).

X is —CH═CHCH(R^(a))CH(R^(a)). In certain embodiments, each R^(a) ishydrogen; in other embodiments, each R^(a) is a substituent other thanhydrogen; in still other embodiments, one R^(a) is hydrogen, and theother is a substituent other than hydrogen.

For example, X is —CH═CH—CH₂— or —CH═CH—CH₂—CH₂— (e.g., in theforegoingmbodiments, the double bond can have the trans configuration;and further each of A and B can be a bond). In certain embodiments, X is—CH═CH—CH₂— (e.g., trans).

c.

In some embodiments, Y is O, NR^(c), or S(O)_(m); e.g., Y is O orNR^(c). Embodiments can include one or more of the following features.

Y is O.

Y is NR^(e) (e.g., R^(e) is C1-C6 alkyl).

A is a bond and/or B is a bond (in some embodiments, each of A and B isa bond).

Each of R^(a) and R^(b) can be as defined anywhere herein (see, forexample, the R^(a) and R^(b) features described above in section[I][A][1][a]).

a is 2 or 3 (e.g., 2) and b is optionally other than 0 (e.g., 1 or 2);in embodiments, A is a bond; or A is other than a bond, e.g., OorNR^(f), e.g., O and B is a bond. Some examples are provided in thefollowing: a is 2 or 3 (e.g., 2), b is 0; and each of A and B is a bond.a is 2 or 3 (e.g., 2), b is other than 0 (e.g., 1 or 2), and each of Aand B is a bond. a is 2 or 3 (e.g., 2), b is other than 0 (e.g., 2 or3), A is other than a bond, e.g., O or NR^(f), e.g., O, and B is a bond.

For example, X is —O—(CH₂)_(2-3(e.g.,2)) or—N(CH₃)—(CH₂)_(2-3(e.g., 2)).

d.

In some embodiments, Y is a bond. Embodiments can include one or more ofthe following features.

A is a bond, O,or NR^(c) (e.g., A is a bond or O, e.g., A is a bond)and/or B is a bond. In certain embodiments, A is a bond and B is a bond.

Each of R^(a) and R^(b) can be as defined anywhere herein (see, forexample, the R^(a) and R^(b) features described above in section[I][A][1][a]).

b is 0 (in embodiments, a can be 1, 2, or 3 (e.g., 1) and one or more ofthe following can apply: A is a bond, A is other than a bond, such as O;B is a bond, each of R^(a) is H; e.g., A is a bond, a is 1, B is a bond;e.g., X is CH₂).

b is 1, 2, or 3 (in embodiments, a can be 1, 2, or 3 and one or more ofthe following can apply: A is a bond, A is other than a bond, such asO;B is a bond, each of R^(a) is H, each of R^(b) is H). In certain ofthese embodiments, X has a span of not more than 4 atoms.

2.

In some embodiments, X is a bond.

B. Variables R4 and R5

In some embodiments, R4 is hydrogen or halo (e.g., chloro).

In some embodiments, R4 is hydrogen.

In some embodiments, R5 is hydrogen.

In some embodiments, each of R4 and R5 is H.

In some embodiments, each of R4 and R5 is a substituent other than H.

C. Variable R1

1.

In some embodiments, R1 is C6-C10 aryl, which is optionally substitutedwith from 1-3 R^(o). In certain embodiments, R1 is phenyl or naphthyl(e.g., phenyl), which is optionally substituted with from 1-3 R^(o) (inembodiments, each R^(o) is independently selected from F, OH, C1-C6alkyl, fluoro(C1-C6) alkyl C3-C6 cycloalkyl, NH₂, C1-C6 alkoxy, C1-C6fluoroalkoxy, and cyano).

In other embodiments, R1 is C8-C10 aryl, which contains a phenyl ringfused to a non-aromatic ring and which is optionally substituted withfrom 1-3 R^(o) (e.g., optionally substituted indanyl or tetralinyl).

2.

In some embodiments, R1 is monocyclic or bicyclic heteroaryl includingfrom 5-10 ring atoms, which is optionally substituted with from 1-3R^(o); wherein from 1-4 of the ring atoms is/are a heteroatomindependently selected from O, N, N—H, N—R^(o), and S.

In certain embodiments, R1 is monocyclic heteroaryl, such as pyridyl.

In other embodiments, R1 is bicyclic heteroaryl, such as those that arefully aromatic such as indolyl and the like.

In still other embodiments, R1 is bicyclic heteroaryl that contains abridgehead nitrogen ring atom and optionally other heteroatom ringatoms, such as indolizinyl, pyrrolopyrimidinyl, pyrazolopyridinyl,imidazopyridinyl, imidazopyriazinyl, triazolopyridinyl,imidazothiazolyl, imidazooxazolyl.

Other examples of R1 heteroaryl groups include, without limitation,pyrazolyl, pyrrolyl, 2-oxo-indolyl, quinolinyl, isoquinolinyl,tetrahydro-isoquinolinyl, benzofuranyl, benzodioxanyl, benzodioxolyl(aka. methylenedioxyphenyl) and corresponding difluoro (CF₂) analog,thiazolyl, 2-oxopyridinyl, pyridinyl N-oxide, pyrimidinyl, thienyl,furanyl, oxazolyl, isoxazolyl, pyridazinyl, imidazolyl, pyrazinyl,isothiazolyl, 1,2-thiazinyl-1,1-dioxide, benzimidazolyl, thiadiazolyl,benzopyranyl, benzothiazolyl, benzotriazolyl, benzoxazolyl,benzothienyl, oxadiazolyl, triazolyl, tetrazolyl, dioxoindolyl (isatin),phthalimido, and the dihydro and tetrahydro congeners of the fullyunsaturated ring systems.

3.

In some embodiments, R1 is heterocyclyl including from 4-10 ring atoms,which is optionally substituted with from 1-3 R^(o); wherein from 1-4 ofthe ring atoms is/are a heteroatom independently selected from O, N,N—H, N—R^(o), and S (e.g., bicyclic heterocyclyl containing a bridgeheadnitrogen ring atom and optionally other heteroatom ring atoms).

Examples of R1 heterocyclyl groups include, without limitation,piperidinyl, morpholinyl, pyrrolidinyl, azetidinyl, azepanyl,isoxazolidinyl, oxazolidinyl , thiazolidinyl, imidazolinyl,quinuclidinyl, isothiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl,thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone,dioxanyl, tropanyl and other bridged bicyclic amines, quiniclidinyl.

4.

In some embodiments, R1 is H.

5.

In some embodiments, R1 is C3-C10 (e.g., C3-C8, C3-C6, C3-C5) cycloalkylor C3-C10 (e.g., C3-C8, C3-C6, C3-C5)cycloalkenyl, each of which isoptionally substituted with from 1-3 R^(o).

In some embodiments, R1 is C3-C10 cycloalkyl, which is optionallysubstituted with from 1-3 R^(o).

In some embodiments, R1 is C3-C8 cycloalkyl, which is optionallysubstituted with from 1-3 R^(o).

In some embodiments, R1 is C3-C6 cycloalkyl, which is optionallysubstituted with from 1-3 R^(o).

In some embodiments, R1 is C3-C5 cycloalkyl, which is optionallysubstituted with from 1-3 R^(o).

In some embodiments, R1 is unsubstituted C3-C10 cycloalkyl. In someembodiments, R1 is unsubstituted C3-C8 cycloalkyl. In some embodiments,R1 is unsubstituted C3-C6 cycloalkyl. In some embodiments, R1 isunsubstituted C3-C5 cycloalkyl.

Examples of R1 cycloalkyl include, without limitation, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 2,6-dimethylcyclohexyl,2,2,6,6-tetramethylcyclohexyl.

In some embodiments, R1 is cyclopropyl, which is optionally substitutedwith from 1-3 R^(o). In some embodiments, R1 is unsubstitutedcyclopropyl.

D. Variables R2 and R3

1.

In some embodiments, R2 is a substituent other than hydrogen (e.g.,phenyl, substituted phenyl, thienyl, thiazolyl, and pyrazol-1-yl), andR3 is hydrogen. In certain embodiments, the compounds can exhibitselectivity for HDAC 1 and/or 2.

2.

In some embodiments, R2 is hydrogen, and R3 is a substituent other thanhydrogen (e.g., fluoro). In certain embodiments, the compounds canexhibit selectivity for HDAC 3.

3.

In some embodiments, each of R2 and R3 is hydrogen.

E. Non-Limiting Combinations

In some embodiments, variables, X, R1, R2, R3, R4, R5, and R^(o) (andtheir attendant sub-definitions) can be combined as provided below:

(a)

X is:

-   -   (i) —Y—[C(R^(a))₂]-A-[C(R^(b))₂]_(b)—B—;    -   (ii) direct bond; or    -   (iii) C═O, C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k),        NR^(k)—SO₂, C(═O)NR^(k) or NR^(k)—C(═O);

R1 is:

-   -   (i) monocyclic or bicyclic heteroaryl including from 5-10 ring        atoms, which is optionally substituted with from 1-3 R^(o);        wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(o), and S;    -   (ii) C6-C10 aryl, which is optionally substituted with from 1-3        R^(o);    -   (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is        optionally substituted with from 1-3 R^(o);    -   (iv) heterocyclyl including from 3-10 ring atoms, which is        optionally substituted with from 1-3 R^(o); wherein from 1-4 of        the ring atoms are a heteroatom independently selected from O,        N, N—H, N—R^(o), and S; or    -   (v) hydrogen;

R^(o) is independently selected from the group consisting of halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—;(C1-C6 alkyl)₂N—; —N*)(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together forma saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atomsare optionally a heteroatom independently selected from NH,N(C1-C6alkyl), O, or S; cyano; phenyl; heteroaryl including from 5-6ring atoms, wherein from 1-4 of the ring atoms are a heteroatomindependently selected from O, N, N—H, N—R^(o″) and S, each of which isoptionally substituted with from 1-3 R^(o″); and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(b)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

R1 is:

-   -   (i) monocyclic or bicyclic heteroaryl including from 5-10 ring        atoms, which is optionally substituted with from 1-3 R^(o);        wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(o), and S;    -   (ii) C6-C10 aryl, which is optionally substituted with from 1-3        R^(o); or    -   (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is        optionally substituted with from 1-3 R^(o);    -   (iv) heterocyclyl including from 3-10 ring atoms, which is        optionally substituted with from 1-3 R^(o); wherein from 1-4 of        the ring atoms are a heteroatom independently selected from O,        N, N—H, N—R^(o), and S; or    -   (v) hydrogen;

R^(o) is independently selected from the group consisting of halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—;(C1-C6 alkyl)₂N—; —N*)(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together forma saturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atomsare optionally a heteroatom independently selected from NH,N(C1-C6alkyl), O, or S; cyano; phenyl; heteroaryl including from 5-6ring atoms, wherein from 1-4 of the ring atoms are a heteroatomindependently selected from O, N, N—H, N—R^(o ″), and S, each of whichis optionally substituted with from 1-3 R^(o″); and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(c)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond;

R1 is:

-   -   (i) monocyclic or bicyclic heteroaryl including from 5-10 ring        atoms, which is optionally substituted with from 1-3 R^(o);        wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(o), and S;    -   (ii) C6-C10 aryl, which is optionally substituted with from 1-3        R^(o); or    -   (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is        optionally substituted with from 1-3 R^(o);    -   (iv) heterocyclyl including from 3-10 ring atoms, which is        optionally substituted with from 1-3 R^(o); wherein from 1-4 of        the ring atoms are a heteroatom independently selected from O,        N, N—H, N—R^(O), and S; or    -   (v) hydrogen;

R^(o) is independently selected from the group consisting of halogen,C1-C6 alkyl, and fluoro(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(d)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

R1 is:

-   -   (i) monocyclic or bicyclic heteroaryl including from 5-10 ring        atoms, which is optionally substituted with from 1-3 R^(o);        wherein from 1-4 of the ring atoms are a heteroatom        independently selected from O, N, N—H, N—R^(o), and S;    -   (ii) C6-C10 aryl, which is optionally substituted with from 1-3        R^(o); or    -   (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which is        optionally substituted with from 1-3 R^(o);    -   (iv) heterocyclyl including from 3-10 ring atoms, which is        optionally substituted with from 1-3 R^(o); wherein from 1-4 of        the ring atoms are a heteroatom independently selected from O,        N, N—H, N—R^(o), and S; or    -   (v) hydrogen;

R^(o) is independently selected from the group consisting of halogen,C1-C6 alkyl, and fluoro(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

-   -   (i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and        R3 is fluoro; or (iii) R2 is a substituent other than hydrogen,        and R3 is hydrogen;

(e)

X is:

-   -   (i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;    -   (ii) direct bond; or    -   (iii) C═O, C(R^(j))₂—C(═O), or C(═O)—C(R^(j))₂, SO₂—NR^(k),        NR^(k)—SO₂, C(═O)NR^(k) and NR^(k)—C(═O);

R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally substitutedwith from 1-3 R^(o);

R^(o) is independently selected from the group consisting of halogen,C1-C6 alkyl, and fluoro(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(f)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]—B—;

R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally substitutedwith from 1-3 R^(o);

R^(o) is independently selected from the group consisting of halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—;(C1-C6 alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together form asaturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms areoptionally a heteroatom independently selected from NH, N(C1-C6alkyl),O, or S; cyano; phenyl; heteroaryl including from 5-6 ring atoms,wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o″), and S, each of which is optionallysubstituted with from 1-3 R^(o″); and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(g)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally substitutedwith from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(h)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond;

R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally substitutedwith from 1-3 R^(o);

R^(o) is independently selected from the group consisting of halogen,C1-C6 alkyl, and fluoro(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(i)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl, optionally substitutedwith from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(j)

X is:

-   -   (i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;    -   (ii) direct bond; or    -   (iii) C═O, C(R^(j))₂—C(═O), or C(═O)—C(R^(j))₂, SO₂—NR^(k),        NR^(k)—SO₂, C(═O)NR^(k) and NR^(k)—C(═O);

R1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S;

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(k)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

R1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S;

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(l)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond;

R1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S;

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(m)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

R1 is monocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S;

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(n)

X is:

(i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

(ii) direct bond; or

(iii) C═O, C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k), NR^(k)—SO₂,C(═O)NR^(k) and NR^(k)—C(═O);

R1 is C6-C10 aryl, optionally substituted with from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(o)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

R1 is C6-C10 aryl, optionally substituted with from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(p)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—;

R1 is C6-C10 aryl, optionally substituted with from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen;

(q)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond;

R1 is C6-C10 aryl, optionally substituted with from 1-3 R^(o);

R^(o) is independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen; or

(r)

X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano;

R1 is C6-C10 aryl, optionally substituted with from 1-3 R^(o);

R^(o) independently selected from the group consisting of: halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano;and SO₂—(C1-C6)alkyl;

R4 is hydrogen or halo;

R5 is hydrogen; and

(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen.

Embodiments can include any one or more of the following features.

The compound or salt according can have formula (Ia):

The compound or salt can have formula (Ib):

A can be a bond.

Each occurrence of R^(a) and R^(b) (when present) can be independentlyselected from H, F, C1-C6 alkyl, and C3-C6 cycloalkyl.

Each occurrence of R^(a) and R^(b) (when present) can be H.

a can be 1.

b can be 0.

a can be 1, and b can be 0. In embodiments, X can be CH₂.

b is 1, 2, or 3. In embodiments, a can also be 1; e.g., X can be(CH₂)₂₋₄.

R1 can be C3-C10 cycloalkyl, which is optionally substituted with from1-3 R^(o); e.g., R1 can be C3-C6 cycloalkyl, which is optionallysubstituted with from 1-3 R^(o); e.g., R1 can be cyclopropyl, which isoptionally substituted with from 1-3 R^(o); e.g., R1 can beunsubstituted C3-C6 cycloalkyl; e.g., R1 can be unsubstitutedcyclopropyl.

In various embodiments, the compound has a structure of formula (Ia) and—X—R₁ is CH₂phenyl, and the phenyl is optionally substituted with one ormore substituents selected from halo (e.g., fluoro) and methyl. In someembodiments, —XR₁ is CH₂pyridyl, and the pyridyl is optionallysubstituted with one or more substituents selected from halo (e.g.,fluoro) and methyl. In some embodiments, —XR₁ is CH₂cycloalkyl (e.g.,cyclopropyl, cyclopentyl, or cyclohexyl). In some cases, —XR₁ isCH₂cyclopropyl. The cycloalkyl can optionally be substituted with one ormore of C1-C3alkyl, C1-C3alkoxy, and halo. In some embodiments, —XR₁ isCH₂pyrazolyl, and the pyrazolyl is optionally substituted with one ormore substituents selected from methyl and halo (e.g., fluoro). Invarious embodiments, R₂ and R₃ are each hydrogen. In some embodiments,R₂ is hydrogen and R₃ is halo (e.g., fluoro). In various embodiments, R₄is hydrogen.

In various embodiments, the compound has a structure of formula (Ib) and—X—R₁ is CH₂phenyl, and the phenyl is optionally substituted with one ormore substituents selected from halo (e.g., fluoro) and methyl. In someembodiments, —XR₁ is CH₂pyridyl, and the pyridyl is optionallysubstituted with one or more substituents selected from halo (e.g.,fluoro) and methyl. In some embodiments, —XR₁ is CH₂cycloalkyl (e.g.,cyclopropyl, cyclopentyl, or cyclohexyl). In some cases, —XR₁ isCH₂cyclopropyl. The cycloalkyl can optionally be substituted with one ormore of C1-C3alkyl, C1-C3alkoxy, and halo. In some embodiments, —XR₁ isCH₂pyrazolyl, and the pyrazolyl is optionally substituted with one ormore substituents selected from methyl and halo (e.g., fluoro). Invarious embodiments, R₂ and R₃ are each hydrogen. In some embodiments,R₂ is hydrogen and R₃ is halo (e.g., fluoro). In various embodiments, R₄is hydrogen.

In some embodiments, the compound or salt disclosed herein can have astructure of formula (2a):

wherein:

-   R1 is C3-C6 cycloalkyl, phenyl, or heteroaryl with 5-6 ring atoms,    wherein R1 is optionally substituted with 1-3 groups independently    selected from Cl, F, and C1-C4 alkyl; and R3 is H or F.

In other embodiments for compounds of formula (2a), R1 is cyclopropyl,phenyl, or heteroaryl with 5-6 ring atoms and 1-2 N atoms, wherein thephenyl and heteroaryl are optionally substituted with 1-2 groupsindependently selected from F, and C1-C4 alkyl. In further embodiments,R1 is cyclopropyl, phenyl, pyridyl, or pyrazolyl, wherein the phenyl,pyridyl and pyrazolyl groups are optionally substituted with 1-2 groupsindependently selected from F, and C1-C4 alkyl.

In various embodiments, the compound or salt disclosed herein has astructure of formula (2b):

wherein:

-   R1 is C3-C6 cycloalkyl, phenyl, or heteroaryl with 5-6 ring atoms,    wherein R1 is optionally substituted with 1-3 groups independently    selected from Cl, F, and C1-C4 alkyl; and R3 is H or F.

In other embodiments for compounds of formula (2b), R1 is cyclopropyl,phenyl, or heteroaryl with 5-6 ring atoms and 1-2 N atoms, wherein thephenyl and heteroaryl are optionally substituted with 1-2 groupsindependently selected from F, and C1-C4 alkyl. In further embodiments,R1 is cyclopropyl, phenyl, pyridyl, or pyrazolyl, wherein the phenyl,pyridyl and pyrazolyl groups are optionally substituted with 1-2 groupsindependently selected from F, and C1-C4 alkyl.

In some embodiments, the compound is one or more of those delineated inTable 1 below. In some embodiments, the compound is one selected fromA1-A16 and A24. In some embodiments, the compound is one selected fromA1-A16. In some embodiments, the compound is selected from A6-A8, A10,Al2, and A24. In some embodiments, the compound is selected from A6-A8,A10, and A12. In some embodiments, the compound is selected from A1,A4-A8, and A13-A15. In some embodiments, the compound is selected fromA2, A3, A9, and A10.

TABLE 1

A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

II. COMPOUND FORMS

Compounds of formula (I) described herein may contain one or moreasymmetric centers and thus occur as racemates and racemic mixtures,single enantiomers, individual diastereomers and diastereomericmixtures. While shown without respect to the stereochemistry in formula(I), compounds disclosed herein include optical isomers enantiomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure stereoisomers; as well as other mixtures of the stereoisomers andpharmaceutically acceptable salts thereof. The use of these compounds isintended to cover the racemic mixture or either of the chiralstereoisomers.

Compounds of formula (I) described herein may also contain linkages(e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amide bonds)wherein bond rotation is restricted about that particular linkage, e.g.restriction resulting from the presence of a ring or double bond.Accordingly, all cis/trans and E/Z isomers and rotational isomers areexpressly included herein.

One skilled in the art will also recognize that it is possible fortautomers to exist for the compounds described herein. Contemplated areall such tautomers even though not shown in the formulas herein. Allsuch isomeric forms of such compounds are expressly included herein.

Optical isomers can be obtained in pure form by standard proceduresknown to those skilled in the art, and include, but are not limited to,diastereomeric salt formation, kinetic resolution, and asymmetricsynthesis. See, for example, Jacques, et al., Enantiomers, Racemates andResolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al.,Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of CarbonCompounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of ResolvingAgents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of NotreDame Press, Notre Dame, Ind. 1972), each of which is incorporated hereinby reference in their entireties. It is also understood that thisdisclosure contemplated all possible regio-isomers, and mixturesthereof, which can be obtained in pure form by standard separationprocedures known to those skilled in the art, and include, but are notlimited to, column chromatography, thin-layer chromatography, andhigh-performance liquid chromatography, for all compounds disclosedherein (e.g., compounds of formula (1), (1a), (1b), (2a) and (2b)).

The compounds described herein also include the various hydrate andsolvate forms of the compounds.

Compounds described herein can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

The compounds described herein also include pharmaceutically acceptablesalts of the compounds disclosed herein. As used herein, the term“pharmaceutically acceptable salt” refers to a salt formed by theaddition of a pharmaceutically acceptable acid or base to a compounddisclosed herein. As used herein, the phrase “pharmaceuticallyacceptable” refers to a substance that is acceptable for use inpharmaceutical applications from a toxicological perspective and doesnot adversely interact with the active ingredient. Pharmaceuticallyacceptable salts, including mono- and bi-salts, include, but are notlimited to, those derived from organic and inorganic acids such as, butnot limited to, acetic, lactic, citric, cinnamic, tartaric, succinic,fumaric, maleic, malonic, mandelic, malic, oxalic, propionic,hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic,pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic,benzoic, and similarly known acceptable acids. Lists of suitable saltsare found in Remington's Pharmaceutical Sciences, 17th ed., MackPublishing Company, Easton, Pa., 1985, p. 1418; Journal ofPharmaceutical Science, 66, 2 (1977); and “Pharmaceutical Salts:Properties, Selection, and Use A Handbook; Wermuth, C. G. and Stahl, P.H. (eds.) Verlag Helvetica Chimica Acta, Zurich, 2002 [ISBN3-906390-26-8] each of which is incorporated herein by reference intheir entireties.

In some embodiments, the compounds are prodrugs. As used herein,“prodrug” refers to a moiety that releases a compound described hereinwhen administered to a patient. Prodrugs can be prepared by modifyingfunctional groups present in the compounds in such a way that themodifications are cleaved, either in routine manipulation or in vivo, tothe parent compounds. Examples of prodrugs include compounds asdescribed herein that contain one or more molecular moieties appended toa hydroxyl, amino, sulfhydryl, or carboxyl group of the compound, andthat when administered to a patient, cleave in vivo to form the freehydroxyl, amino, sulfhydryl, or carboxyl group, respectively. Examplesof prodrugs include, but are not limited to, acetate, formate andbenzoate derivatives of alcohol and amine functional groups in thecompounds described herein. Preparation and use of prodrugs is discussedin T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencein their entireties.

III. SYNTHESIS OF COMPOUNDS OF FORMULA (I)

The compounds described herein can be prepared in a variety of waysknown to one skilled in the art of organic synthesis. The compoundsdescribed herein can be synthesized using the methods as hereinafterdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry or variations thereon as appreciated bythose skilled in the art.

In some embodiments, the compounds described herein can be preparedusing the starting materials indicated in Table 2 below and theappropriately substituted indazole.

TABLE 2 R-X or Compound aldehyde diamine MS NMR A1 

ES⁺ (M + H)⁺ 344 ¹H NMR (DMSO-d₆) δ: 10.60 (s, 1H), 8.83 (s, 1H), 8.78(m, 1H), 8.65 (s, 1H), 8.37 (s, 1H), 8.17 (d, J = 8.7 Hz, 2H), 7.97 (d,J = 8.7, 1H), 7.86 (m, 1H), 7.58 (d. J = 8.1 Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.4-7.3 (m, 2H), 5.93 (s, 2H) A2 

ES⁺ (M + H)⁺ 343 ¹H NMR (DMSO-d₆) δ: 10.34 (br. s, 1H), 8.56 (s, 1H),8.31 (s, 1H), 8.04 (d, J = 9 Hz, 1H), 7.84 (d, J = 9 Hz, 1H), 7.44 (br.d, 1H), 7.35-7.15 (m, 8H), 5.72 (s, 2H) A3 

ES⁺ (M + H)⁺ 347 ¹H NMR (DMSO-d₆) δ: 10.60 (s, 1H), 8.60 (s, 1H), 8.24(s, 1H), 8.11 (d, J = 9 Hz, 1H), 7.89 (d, J = 9 Hz, 1H), 7.68 (s, 1H),7.58 (br. d, J = 7.8, 1H), 7.5-7.3 (m, 4H), 5.53 (s, 2H), 3.73 (s, 3H)A4 

ES⁺ (M + H)⁺ 362 ¹H NMR (CD₃OD) δ: 8.72 (br. s, 1H), 8.63 (m, 1H), 8.58(s, 1H), 8.34 (s, 1H), 8.17 (dd, J = 9, 1.5 Hz, 1H), 7.90 (m, 1H), 7.85(d. J = 9 Hz, 1H), 7.6-7.4 (m, 4H), 5.92 (s, 2H) A5 

ES⁺ (M + H)⁺ 372 ¹H NMR (CD₃OD) δ: 8.65 (s, 1H), 8.33 (br. s, 1H), 8.18(d, J = 8.7 Hz, 1H), 7.90 (2 d, J = 8.7, 8.1 Hz, 2H), 7.66 (d. J = 8.1Hz, 1H), 7.6-7.4 (m, 4H), 5.91 (s, 2H), 2.86 (s, 3H), 2.74 (s, 3H) A6 

ES⁺ (M + H)⁺ 362 ¹H NMR (CD₃OD) δ: 8.88 (s, 1H), 8.83 (d, J = 5.7 Hz,1H), 8.61 (s, 1H), 8.52 (d, J = 8.1 Hz, 1H), 8.34 (s, 1H), 8.16 (dd, J =8.7, 1.5 Hz, 1H), 8.08 (dd, J = 8.1, 6 Hz, 1H),7.87 (d. J = 8.7 Hz, 1H),7.46 (m, 1H), 7.18 (m, 2H), 5.99 (s, 2H) A7 

ES⁺ (M + H)⁺ 380 ¹H NMR (CD₃OD) δ: 8.71 (br. s, 1H), 8.62 (m, 1H), 8.57(s, 1H), 8.33 (s, 1H), 8.15 (dd, J = 8.7, 1.5 Hz, 1H), 7.99 (br. m, 1H),7.83 (d. J = 8.7 Hz, 1H), 7.53 (m, 1H), 7.38- 7.24 (m, 2H), 5.91 (s, 2H)A8 

ES⁺ (M + H)⁺ 390 ¹H NMR (CD₃OD) δ: 8.62 (s, 1H), 8.32 (s, 1H), 8.16 (dd,J = 9, 1.5 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H),7.66 (d. J = 8.4 Hz, 1H), 7.48 (br. m, 1H), 7.21 (br. m, 2H), 5.90 (s,2H), 2.86 (s, 3H), 2.75 (s, 3H) A9 

ES⁺ (M + H)⁺ 379 ¹H NMR (CD₃OD) δ: 8.60 (m, 1H), 8.28 (s, 1H), 8.11 (dd,J = 9, 1.5 Hz, 1H), 7.73 (d, J = 9 Hz, 1H), 7.6-7.4 (m, 4H), 7.3-7.0 (m,3H), 5.69 (s, 2H) A10

ES⁺ (M + H)⁺ 397 ¹H NMR (CD₃OD) δ: 8.58 (m, 1H), 8.27 (s, 1H), 8.09 (dd,J = 9, 1.5 Hz, 1H), 7.72 (d, J = 9 Hz, 1H), 7.48 (br. dd, 1H), 7.3-7.0(m, 5H), 5.69 (s, 2H) A11

ES⁺ (M + H)⁺ 307 ¹H NMR (DMSO-d₆) δ: 10.59 (s, 1H), 8.60- 8.65 (m, 1H),8.27 (d, J = 0.8 Hz, 1H), 8.11 (dd, J = 8.8, 1.6 Hz, 1H), 7.85 (d, J =8.9 Hz, 1H), 7.33-7.62 (m, 4H), 4.37 (d, J = 7.0 Hz, 2H), 1.25-1.36 (m,1H), 0.47-0.54 (m, 2H), 0.38-0.44 (m, 2H) A12

ES⁺ (M + H)⁺ 325 ¹H NMR (CD₃OD) δ: 8.57 (s, 1H), 8.21 (s, 1H), 8.10 (dd,J = 9, 1.5 Hz, 1H), 7.75 (d, J = 9 Hz, 1H), 7.52 (dd, J = 9, 5.1 Hz,1H), 7.35-7.25 (m, 2H), 4.38 (d, J = 6.9 Hz, 2H), 1.35 (m, 1H), 0.57 (m,2H), 0.45 (m, 2H) A13

ES⁺ (M + H)⁺ 344 ¹H NMR (DMSO-d₆) δ: 10.59 (s, 1H), 8.96 (br. s, 1H),8.89 (s, 1H), 8.84 (br. d, 1H), 8.71 (s, 1H), 8.41 (br. d, 1H), 7.96(dd, 1H), 7.91 (d, J = 9 Hz, 1H), 7.68 (d. J = 9 Hz, 1H), 7.61 (d, J =7.8 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 1H), 7.33(t, J = 7.8 Hz, 1H), 5.94 (s, 2H) A14

ES⁺ (M + H)⁺ 362 ¹H NMR (CD₃OD) δ: 8.76 (s, 2H), 8.67 (s, 1H), 8.62 (m,1H), 8.09 (m, 1H), 7.98 (dd, J = 9, 1.5 Hz, 1H), 7.74 (d. J = 9 Hz, 1H),7.6- 7.4 (m, 4H), 5.92 (s, 2H) A15

ES⁺ (M + H)⁺ 372 ¹H NMR (CD₃OD) δ: 8.77 (s, 1H), 8.63 (dd, J = 1.8, 0.9Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.97 (dd, J = 9, 1.8 Hz, 1H), 7.71 (2d. J = 9, 8.4 Hz, 2H), 7.6- 7.4 (m, 4H), 5.96 (s, 2H), 2.87 (s, 3H),2.76 (s, 3H) A16

ES⁺ (M + H)⁺ 307 ¹H NMR (DMSO-d₆) δ: 10.61 (s, 1H), 8.70 (dd, J = 1.6,0.8 Hz, 1H), 8.69 (d, J = 0.7 Hz, 1H), 7.93 (dd, J = 9.1, 1.7 Hz, 1H),7.71 (d, J = 9.0 Hz, 1H), 7.34- 7.67 (m, 4H), 4.34 (d, J = 7.3 Hz, 2H),1.38- 1.48 (m, 1H), 0.56- 0.61 (m, 2H), 0.45- 0.50 (m, 2H)

Compounds described herein can be conveniently prepared in accordancewith the procedures outlined in the Examples section, from commerciallyavailable starting materials, compounds known in the literature, orreadily prepared intermediates, by employing conventional syntheticmethods and procedures known to those skilled in the art. Conventionalsynthetic methods and procedures for the preparation of organicmolecules and functional group transformations and manipulations can bereadily obtained from the relevant scientific literature or fromstandard textbooks in the field. It will be appreciated that, wheretypical or preferred process conditions (i.e., reaction temperatures,times, mole ratios of reactants, solvents, pressures, etc.) are given,other process conditions can also be used unless otherwise stated.Optimum reaction conditions may vary with the particular reactants orsolvent used, but such conditions can be determined by one skilled inthe art by routine optimization procedures. Those skilled in the art oforganic synthesis will recognize that the nature and order of thesynthetic steps presented may be varied for the purpose of optimizingthe formation of the compounds described herein.

Synthetic chemistry transformations useful in synthesizing the compoundsdescribed herein are known in the art and include, for example, thosesuch as described in R. C. Larock, Comprehensive OrganicTransformations, 2d.ed., Wiley-VCH Publishers (1999); P. G. M. Wuts andT. W. Greene, Protective Groups in Organic Synthesis, 4th Ed., JohnWiley and Sons (2007); L. Fieser and M. Fieser, Fieser and Fieser'sReagents for Organic Synthesis, John Wiley and Sons (1994); and L.Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof. Preparation ofcompounds can involve the protection and deprotection of variouschemical groups. The need for protection and deprotection, and theselection of appropriate protecting groups can be readily determined byone skilled in the art. The chemistry of protecting groups can be found,for example, in Wuts P G M and Greene T W, 2006, Greene's ProtectiveGroups in Organic Synthesis, Fourth Edition, John Wiley & Sons, Inc.,Hoboken, N.J., USA, which is incorporated herein by reference in itsentirety. Adjustments to the protecting groups and formation andcleavage methods described herein may be adjusted as necessary in lightof the various substituents.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,i.e., temperatures which can range from the solvent freezing temperatureto the solvent boiling temperature. A given reaction can be carried outin one solvent or a mixture of more than one solvent. Depending on theparticular reaction step, suitable solvents for a particular reactionstep can be selected.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H and/or ¹³C NMR) infrared spectroscopy,spectrophotometry (e.g., UV-visible), or mass spectrometry, or bychromatography such as high performance liquid chromatography (HPLC) orthin layer chromatography.

The compounds described herein can be separated from a reaction mixtureand further purified by a method such as column chromatography,high-performance liquid chromatography (HPLC), or recrystallization.

One of skill in the art will recognize that there are additional methodsof producing the compounds of formula (I) in addition to those describedin the Examples section.

IV. USE

A histone deacetylase (HDAC), as described herein, can be anypolypeptide having features characteristic of polypeptides that catalyzethe removal of the acetyl group (deacetylation) from acetylated targetproteins. Features characteristic of HDACs are known in the art (see,for example, Finnin et al., 1999, Nature, 401:188). Thus, an HDAC can bea polypeptide that represses gene transcription by deacetylating theε-amino groups of conserved lysine residues located at the N-termini ofhistones, e.g., H3, H4, H2A, and H2B, which form the nucleosome. HDACsalso deacetylate other proteins such as p53, E2F, α-tubulin, and MyoD(see, for example, Annemieke et al., 2003, Biochem. J., 370:737). HDACscan also be localized to the nucleus and certain HDACs can be found inboth the nucleus and also the cytoplasm.

Compounds of formula (I) described herein may interact with any HDAC. Insome embodiments, the compounds of formula (I) described herein willhave at least about 2-fold (e.g., at least about 5-fold, 10-fold,15-fold, or 20-fold) greater activity to inhibit one or more class IHDACS (e.g., HDAC1, HDAC2, or HDAC3) as compared to one or more otherHDACs (e.g., one or more HDACs of class IIa, IIb, or IV).

In various embodiments, the compound of formula (I) is selective forHDAC 1, compared to HDAC2 and HDAC3. In various embodiments, thecompound of formula (I) is selective for HDAC 2, compared to HDAC1 andHDAC3. In various embodiments, the compound of formula (I) is selectivefor HDAC 3, compared to HDAC1 and HDAC2. In various embodiments, thecompound of formula (I) is selective for HDAC1 and HDAC2, compared toHDAC3. In various embodiments, the compound of formula (I) is selectivefor HDAC1 and HDAC3, compared to HDAC2. In various embodiments, thecompound of formula (I) is selective for HDAC2 and HDAC3, compared toHDAC1.

One aspect features a method of treating a cancer in patient in needthereof, comprising administering a therapeutically effective amount ofan HDAC inhibitor as described herein, or pharmaceutically, acceptablesalt thereof. In some embodiments, the cancer is a solid tumor,neoplasm, carcinoma, sarcoma, leukemia, or lymphoma. In someembodiments, leukemias include acute leukemias and chronic leukemiassuch as acute lymphocytic leukemia (ALL), B-cell acute lymphoblasticleukemia (B-ALL), acute myeloid leukemia, chronic lymphocytic leukemia(CLL), chronic myelogenous leukemia (CML) and Hairy Cell Leukemia;lymphomas such as cutaneous T-cell lymphomas (CTCL), noncutaneousperipheral T-cell lymphomas, lymphomas associated with human T-celllymphotrophic virus (fITLV) such as adult T-cell leukemia/lymphoma(ATLL), Hodgkin's disease and non-Hodgkin's lymphomas, large-celllymphomas, diffuse large B-cell lymphoma (DLBCL); Burkitt's lymphoma;primary central nervous system (CNS) lymphoma; multiple myeloma;childhood solid tumors such as brain tumors, neuroblastoma,retinoblastoma, Wilm's tumor, bone tumors, and soft-tissue sarcomas,common solid tumors of adults such as head and neck cancers (e.g., oral,laryngeal and esophageal), genitor-urinary cancers (e.g., prostate,bladder, renal, uterine, ovarian, testicular, rectal and colon), lungcancer, breast cancer.

In some embodiments, the cancer is (a) Cardiac: sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; (b) Lung: bronchogenic carcinoma (squamouscell, undifferentiated small cell, undifferentiated large cell,adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma,sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; (c)Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma,leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel(adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma,leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel(adenocarcinoma, tubular adenoma, villous adenoma, hamartoma,leiomyoma); (d) Genitourinary tract: kidney (adenocarcinoma, Wilm'stumor (nephroblastoma), lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); (e) Liver: hepatoma (hepatocellular carcinoma),cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellularadenoma, hemangioma; (f) Bone: osteogenic sarcoma (osteosarcoma),fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing'ssarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma,malignant giant cell tumor chordoma, osteochrondroma (osteocartilaginousexostoses), benign chondroma, chondroblastoma, chondromyxofibroma,osteoid osteoma and giant cell tumors; (g) Nervous system: skull(osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges(meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma,medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastomamultiform, oligodendroglioma, schwannoma, retinoblastoma, congenitaltumors), spinal cord (neurofibroma, meningioma, glioma, sarcoma); (h)Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma,serous cystadenocarcinoma, mucinous cystadenocarcinoma), unclassifiedcarcinoma (granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoidsarcoma), embryonal rhabdomyosarcoma, fallopian tubes (carcinoma); (i)Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma (malignant lymphoma); (j) Skin:malignant melanoma, basal cell carcinoma, squamous cell carcinoma,Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma,dermatofibroma, keloids, psoriasis; and (k) Adrenal glands:neuroblastoma conditions.

In another aspect, provided is a method of treating an inflammatorydisorder in patient in need thereof, comprising administering atherapeutically effective amount of a compound of formula (I) asdescribed herein, or pharmaceutically, acceptable salt thereof. In someembodiments, the inflammatory disorder is an acute and chronicinflammatory disease, autoimmune disease, allergic disease, diseaseassociated with oxidative stress, and diseases characterized by cellularhyperproliferation. Non-limiting examples are inflammatory conditions ofa joint including rheumatoid arthritis (RA) and psoriatic arthritis;inflammatory bowel diseases such as Crohn's disease and ulcerativecolitis; spondyloarthropathies; scleroderma; psoriasis (including T-cellmediated psoriasis) and inflammatory dermatoses such an dermatitis,eczema, atopic dermatitis, allergic contact dermatitis, urticaria;vasculitis (e.g., necrotizing, cutaneous, and hypersensitivityvasculitis); eosinophilic myositis, eosinophilic fasciitis; cancers withleukocyte infiltration of the skin or organs, ischemic injury, includingcerebral ischemia (e.g., brain injury as a result of trauma, epilepsy,hemorrhage or stroke, each of which may lead to neurodegeneration); HIV,heart failure, chronic, acute or malignant liver disease, autoimmunethyroiditis; systemic lupus erythematosus, Sjorgren's syndrome, lungdiseases (e.g., ARDS); acute pancreatitis; amyotrophic lateral sclerosis(ALS); Alzheimer's disease; cachexia/anorexia; asthma; atherosclerosis;chronic fatigue syndrome, fever; diabetes (e.g., insulin diabetes orjuvenile onset diabetes); glomerulonephritis; graft versus hostrejection (e.g., in transplantation); hemorrhagic shock; hyperalgesia:inflammatory bowel disease; multiple sclerosis; myopathies (e.g., muscleprotein metabolism, esp. in sepsis); osteoarthritis; osteoporosis;Parkinson's disease; pain; pre-term labor; psoriasis; reperfusioninjury; cytokine-induced toxicity (e.g., septic shock, endotoxic shock);side effects from radiation therapy, temporal mandibular joint disease,tumor metastasis; or an inflammatory condition resulting from strain,sprain, cartilage damage, trauma such as burn, orthopedic surgery,infection or other disease processes.

Allergic diseases and conditions, include but are not limited torespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic pneumonias (e.g., Loeffler's syndrome, chronic eosinophilicpneumonia), delayed-type hypersensitivity, interstitial lung diseases(ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated withrheumatoid arthritis, systemic lupus erythematosus, ankylosingspondylitis, systemic sclerosis, Sjogren's syndrome, polymyositis ordermatomyositis); systemic anaphylaxis or hypersensitivity responses,drug allergies (e.g., to penicillin, cephalosporins), insect stingallergies, and the like.

In another aspect, provided is a method of preventing or treating amemory-related disorder in patient in need thereof, comprisingadministering a therapeutically effective amount of a compound offormula (I) as described herein, or pharmaceutically, acceptable saltthereof. Compounds of formula (I) can be used to treat patients withmemory impairments associated with direct cognitive disorders such asamnesia, dementia and delirium; anxiety disorders such as phobias, panicdisorders, psychosocial stress (e.g. as seen in disaster, catastrophe orviolence victims), obsessive-compulsive disorder, generalized anxietydisorder and post-traumatic stress disorder; mood disorders such asdepression and bipolar disorder; and psychotic disorders such asschizophrenia and delusional disorder. Memory impairment, a hallmark ofneurodegenerative diseases such as, but not limited to, Parkinson's,Alzheimer's, Huntington's, amyotrophic lateral sclerosis (ALS),spinocerebellar ataxia, as well as aging, can also be treated by usingcompounds of formula (I). In addition, compounds as disclosed herein canbe used to treat drug addiction through extinction of drug-seekingbehavior.

In another aspect, the present disclosure provides a method ofpreventing or treating a hemoglobin disorder in patient in need thereof,comprising administering a therapeutically effective amount of acompound of formula (I) as described herein, or pharmaceutically,acceptable salt thereof. Compounds of formula (I) can be used to treatpatients with sickle cell anemia or β-thalassemia. In various cases, thecompound is a selective HDAC 1 and/or HDAC 2 inhibitor and is used toprevent or treat the hemoglobin disorder (e.g., sickle cell anemia orβ-thalassemia).

In a further aspect, this application features methods of treating aneurological condition (e.g., Friedreich's ataxia (FRDA), myotonicdystrophy, spinal muscular atrophy, fragile X syndrome, Huntington'sdisease, a spinocerebellar ataxia, Kennedy's disease, amyotrophiclateral sclerosis, Niemann Pick, Pitt Hopkins disease, spinal and bulbarmuscular atrophy, Alzheimer's disease or schizophrenia, bipolardisorder, and related diseases) that include administering a compound offormula (I) described herein to a patient having a neurologicalcondition.

In another aspect, this application features the use of a compound offormula (I) described herein in the preparation of a medicament for thetreatment or prevention of a neurological condition (e.g., Friedreich'sataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome,Huntington's disease, a spinocerebellar ataxia, Kennedy's disease,amyotrophic lateral sclerosis, Niemann Pick, Pitt Hopkins disease,spinal and bulbar muscular atrophy, or Alzheimer's disease); amemory-affecting condition or disease, a cancer; or an inflammatorydisorder, or a Plasmodium falciparum infection (e.g., malaria).

In a further aspect, the application provides a kit for the treatment orprevention of a disorder selected from a neurological disorder (e.g.,Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy,fragile X syndrome, Huntington's disease, a spinocerebellar ataxia,Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbarmuscular atrophy, or Alzheimer's disease), a memory-affecting conditionor disease, a cancer, an inflammatory disorder, or a Plasmodiumfalciparum infection (e.g., malaria) in a patient in need thereof,comprising (i) a compound of formula (I) described herein or apharmaceutically acceptable salt thereof; and (ii) instructionscomprising a direction to administer said compound to said patient.

In some embodiments of the above methods, the methods further includeassaying the activity of the candidate compound to increase expressionof one or more genes whose expression is decreased in the neurologicalcondition (e.g., frataxin, huntingtin, brain derived neurotrophic factor(BDNF), peroxisome proliferator-activated receptor-gamma, coactivator 1,alpha (PGC1A), ataxin, fragile X mental retardation (FMR1), dystrophiamyotonica protein kinase (DMPK), or androgen receptor). In someembodiments, the activity of the candidate compound to increaseexpression of one or more genes whose expression is decreased in theneurological condition is measured in an animal, e.g., an animal modelof the neurological condition.

In some embodiments of the above methods, the method is repeated for aplurality of test compounds (e.g., at least 10, 20, 50, 100, 200, 500,or 1000 test compounds).

In another aspect, this application features methods of treating aneurological condition (e.g., Friedreich's ataxia, myotonic dystrophy,spinal muscular atrophy, fragile X syndrome, Huntington's disease,spinocerebellar ataxias, Kennedy's disease, amyotrophic lateralsclerosis, spinal and bulbar muscular atrophy, or Alzheimer's disease)that include performing any of the above methods, formulating thecandidate compound in a pharmaceutical composition, and administeringthe pharmaceutical composition to a patient having a neurologicalcondition.

HDAC inhibitors have been shown to have antimalarial activity (Andrewset al., 2000, Int. J. Parasitol., 30:761-768; Andrews et al.,Antimicrob. Agents Chemother., 52:1454-61). Certain embodiments includemethods of treating a Plasmodium falciparum infection (e.g., malaria) ina patient in need thereof.

HDAC inhibitors may also be useful to treat infectious disease such asviral infections. For example, treatment of HIV infected cells with HDACinhibitors and anti-retroviral drugs can eradicate virus from treatedcells (Blazkova j et al J Infect Dis. 2012 Sep. 1; 206(5):765-9; ArchinN M et al Nature 2012 Jul. 25, 487(7408):482-5). Certain embodimentsinclude methods of treating a HIV infection in subjects in need thereof.

V. PHARMACEUTICAL COMPOSITIONS

HDAC inhibitors can be administered neat or formulated as pharmaceuticalcompositions. Pharmaceutical compositions include an appropriate amountof the HDAC inhibitor in combination with an appropriate carrier andoptionally other useful ingredients.

Acceptable salts of the formula (I) compounds described herein include,but are not limited to, those prepared from the following acids: alkyl,alkenyl, aryl, alkylaryl and alkenylaryl mono-, di- and tricarboxylicacids of 1 to 20 carbon atoms, optionally substituted by 1 to 4hydroxyls; alkyl, alkenyl, aryl, alkylaryl and alkenylaryl mono-, di-and trisulfonic acids of 1 to 20 carbon atoms, optionally substituted by1 to 4 hydroxyls; dibasic acids and mineral acids. Examples includehydrochloric; hydrobromic; sulfuric; nitric; phosphoric; lactic(including (+)−L-lactic, (+/−)-DL-lactic); fumaric; glutaric; maleic;acetic; salicyclic; p-toluenesulfonic; tartaric (including(+)−L-tartaric); citric; methanesulfonic; formic; malonic; succinic;naphthalene-2-sulfonic; and benzenesulfonic acids. Also,pharmaceutically-acceptable salts can be prepared as amine salts,ammonium salts, or alkaline metal or alkaline earth salts, such assodium, potassium or calcium salts of the carboxylic acid group. Theseare formed from alkaline metal or alkaline earth metal bases or fromamine compounds.

Pharmaceutical compositions of formula (I) compounds described hereinsuitable for oral administration can be in the form of (1) discreteunits such as capsules, sachets, tablets, or lozenges each containing apredetermined amount of the HDAC inhibitor; (2) a powder or granules;(3) a bolus, electuary, or paste; (4) a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or (5) an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. Compositions suitable fortopical administration in the mouth, for example buccally orsublingually, include lozenges. Compositions suitable for parenteraladministration include aqueous and non-aqueous sterile suspensions orinjection solutions. Compositions suitable for rectal administration canbe presented as a suppository.

Pharmaceutical compositions of formula (I) compounds described hereincan be formulated using a solid or liquid carrier. The solid or liquidcarrier should be compatible with the other ingredients of theformulation and not deleterious to the recipient. If the pharmaceuticalcomposition is in tablet form, then the HDAC inhibitor is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. If thecomposition is in powder form, the carrier is a finely divided solid inadmixture with the finely divided active ingredient. The powders andtablets can contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, lowmelting waxes and ion exchange resins. A solid carrier can include oneor more substances that can act as flavoring agents, lubricants,solubilizers, suspending agents, fillers, glidants, compression aids,binders or tablet-disintegrating agents. A suitable carrier can also bean encapsulating material.

If the composition is a solution, suspension, emulsion, syrup, elixir,or pressurized composition, then liquid carriers can be used. In thiscase, the HDAC inhibitor is dissolved or suspended in a pharmaceuticallyacceptable liquid carrier. Suitable examples of liquid carriers for oraland parenteral administration include (1) water; (2) alcohols, e.g.monohydric alcohols and polyhydric alcohols such as glycols, and theirderivatives; and (3) oils, e.g. fractionated coconut oil and arachisoil. For parenteral administration, the carrier can also be an oilyester such as ethyl oleate and isopropyl myristate. Liquid carriers forpressurized compositions include halogenated hydrocarbon or otherpharmaceutically acceptable propellants. The liquid carrier can containother suitable pharmaceutical additives such as solubilizers;emulsifiers; buffers; preservatives; sweeteners; flavoring agents;suspending agents; thickening agents; colors; viscosity regulators;stabilizers; osmo-regulators; cellulose derivatives such as sodiumcarboxymethyl cellulose; antioxidants; and bacteriostatics. Othercarriers include those used for formulating lozenges such as sucrose,acacia, tragacanth, gelatin and glycerin as well as those used informulating suppositories such as cocoa butter or polyethylene glycol.

If the composition is to be administered intravenously orintraperitoneally by infusion or injection, solutions of the HDACinhibitor can be prepared in water, optionally mixed with a nontoxicsurfactant. Dispersions can also be prepared in glycerol, liquidpolyethylene glycols, triacetin, and mixtures thereof and in oils. Underordinary conditions of storage and use, these preparations contain apreservative to prevent the growth of microorganisms. The compositionsuitable for injection or infusion can include sterile aqueous solutionsor dispersions or sterile powders comprising the active ingredient,which are adapted for the extemporaneous preparation of sterileinjectable or infusible solutions or dispersions, optionallyencapsulated in liposomes. In all cases, the ultimate dosage form shouldbe sterile, fluid and stable under the conditions of manufacture andstorage. The liquid carrier or vehicle can be a solvent or liquiddispersion medium as described above. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin. Sterileinjectable solutions are prepared by incorporating the HDAC inhibitor inthe required amount in the appropriate solvent with some of the otheringredients enumerated above, as required, followed by filtersterilization. In the case of sterile powders for the preparation ofsterile injectable solutions, the preferred methods of preparation arevacuum drying and the freeze-drying techniques, which yield a powder ofthe HDAC inhibitor, plus any additional desired ingredient present inthe previously sterile-filtered solutions.

Pharmaceutical compositions can be in unit-dose or multi-dose form or ina form that allows for slow or controlled release of the HDAC inhibitor.Each unit-dose can be in the form of a tablet, capsule or packagedcomposition such as, for example, a packeted powder, vial, ampoule,prefilled syringe or sachet containing liquids. The unit-dose form alsocan be the appropriate number of any such compositions in package form.Pharmaceutical compositions in multi-dose form can be packaged incontainers such as sealed ampoules and vials. In this case, the HDACinhibitor can be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of a sterile liquid carrier immediatelyprior to use. In addition, extemporaneous injection solutions andsuspensions can be prepared from sterile powders, granules and tabletsof the kind previously described.

VI. EXAMPLES

Synthesis of Formula (I) Compounds/General Synthetic Scheme

Compounds described herein, of formulae (Ia) and (Ib), where R1, X, R2,R3, R4, R5 are defined as described anywhere herein, can be obtained byreaction of an optionally substituted indazole carboxylate ester (R₇e.g. C₁-C₄ alkyl, phenyl, benzyl, allyl) with an R₁—X— containing moietyusing methods well known by those skilled in the art, such as, but notlimited to, Heck coupling, Suzuki coupling, alkylation, acylation (seefor example Joule J A and Mills K, Heterocyclic Chemistry, FifthEdition, John Wiley & Sons, Inc., Hoboken, N.J., USA). The substitutedor unsubstituted indazole carboxylate can be prepared by methods wellknown to those skilled in the art and summarized for example in Wiley R.H., Behr L. C., Fusco R., Jarboe C. H., Chemistry of HeterocyclicCompounds: Pyrazoles, Pyrazolines, Pyrazolidines, Indazoles andCondensed Rings, Volume 22, John Wiley & Sons, Inc., Hoboken, N.J., USA.Alternatively R₁—X substitution can be introduced when the indazole ringis built. After deprotection of ester COOR₇ (using a method appropriatefor R₇ such as, but not limited to, saponification, hydrogenation, acidhydrolysis) a substituted or unsubstituted N-(o-aminophenyl)amide isprepared by an amide-forming reaction of the acrylic acid with aprotected or unprotected substituted or unsubstitutedo-phenylenediamine, where P is a protecting group as defined in Wuts P GM and Greene T W, 2006, Greene's Protective Groups in Organic Synthesis,Fourth Edition, John Wiley & Sons, Inc., Hoboken, N.J., USA.Alternatively, the indazole ester can be deprotected to generate acarboxylic acid which can be reacted with a protected or unprotected,substituted or unsubstituted, o-phenylenediamine. The intermediate amidecan then be reacted with a reagent delivering the R₁—X moiety usingmethods well known to those skilled in the art as described above.Compounds disclosed herein can be obtained after deprotection ifrequired using methods well known to those skilled in the art and whichare described for example in Wuts P G M and Greene T W, 2006, Greene'sProtective Groups in Organic Synthesis, Fourth Edition, John Wiley &Sons, Inc., Hoboken, N.J., USA.

Example 1 Synthesis ofN-(2-aminophenyl)-1-((5-fluoropyridin-3-yl)methyl)-1-H-indazole-5-carboxamide,A4

Methyl indazole-5-carboxylate: Isoamyl nitrite (26.8 g, 22.8 mmol) wasadded to a mixture of methyl 4-amino-3-methylbenzoate (3.4 g, 20.8 mmol)in acetic acid (AcOH, (20 mL). The reaction mixture was stirred at roomtemperature for lh then at 80° C. for 5 h. It was concentrated and theresidue was purified by silica gel column chromatography (Hexanes/EtOAc10:1 to 2:1) to give pure methyl 1H-indazole-5-carboxylate.

Methyl 1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylate: To asolution of methyl 1H-indazole-5-carboxylate (694 mg, 3.94 mmol) in DMF(20 mL) was added 3-(chloromethyl)-5-fluoropyridine (3.94 mmol, 1.2 eq,prepared from the alcohol with SOCl₂) and Cs₂CO₃ (3.85 g) at roomtemperature. After stirring 3 h at 65° C., the reaction mixture wasquenched with aqueous ammonium chloride. The mixture (combined with asmall scale reaction) was diluted with H₂O, extracted withdichloromethane, washed with sat. NaHCO₃ and brine. It was then driedover Na₂SO₄, filtered, and concentrated. The residue was purified bycolumn chromatography (Hexanes:EtOAc 7:1 to 0:1) to give regioisomericproducts methyl1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylate (422 mg) andmethyl 2-((5-fluoropyridin-3-yl)methyl)-2H-indazole-5-carboxylate (230mg), the former being carried forward in this synthetic protocol, thelatter being used to form regioisomerN-(2-aminophenyl)-2-((5-fluoropyridin-3-yl)methyl)-2H-indazole-5-carboxamideA14.

1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylic acid: AqueousNaOH (3N, 2 mL) was added to a solution of methyl1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylate (422 mg, 0.94mmol) in MeOH/THF (1:1, 10 mL) at room temperature and the mixture wasstirred overnight. After removal of the organic solvents under reducedpressure, the resulting aqueous phase was acidified to pH=2-3. The solidwas collected by filtration and dried to give methyl1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxylate (328 mg).

tert-Butyl(2-(1((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxamido)phenyl)carbamate: HATU (185 mg, 1.5 eq), DIPEA (0.226 mL), andtert-butyl (2-aminophenyl)carbamate (81 mg, 1.2 eq) were added to asolution of the acid prepared as described above (100 mg, 0.325 mmol) inDMF (3 mL) at 0° C. The mixture was allowed to warm up and was stirredfor 16 h. It was quenched with aqueous ammonium chloride, diluted withwater, extracted with dichloromethane, and washed with sat. NaHCO₃ andbrine. It was then dried over Na₂SO₄, filtered, and concentrated. Theresidue was purified by preparative HPLC to yield product tert-butyl(2-(1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxamido)phenyl)carbamate(130 mg).

N-(2-aminophenyl)-1-((5-fluoropyridin-3-yl)methyl)-1H-indazole-5-carboxamide,A4: The Boc-protected material (130 mg) was deprotected by incubationwith HCl (4M in dioxane, 1 mL) in dioxane (3 mL) and MeOH (1 mL) at 0°C. for 2 h followed by overnight at room temperature. The mixture wasthen concentrated and the HC salt precipitated. It was filtered andwashed with MeOH/EtOAc to yield A4 as the HCl salt (106 mg). HPLC/UV:purity>97%. LC/MS: m/z 362 (M+H)⁺¹H NMR (CD₃OD) δ: 8.72 (br. s, 1H),8.63 (m, 1H), 8.58 (s, 1H), 8.34 (s, 1H), 8.17 (dd, J=9, 1.5 Hz, 1H),7.90 (m, 1H), 7.85 (d. J=9 Hz, 1H), 7.6-7.4 (m, 4H), 5.92 (s, 2H).

HDAC Enzyme Inhibition

The HDAC activity inhibition assay was performed as follows to determinethe ability of a test compound to inhibit HDAC enzymatic activity.Serial dilutions of HDAC inhibitors were prepared in HDAC assay buffer(25 mM Tris/HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, mM MgCl₂, pH 8) in96-well assay plates (Fisher scientific, #07-200-309) and werepre-incubated for 2 hours at room temperature in the presence of 125μg/ml BSA and purified HDAC1 (BPS Bioscience, San Diego, Calif. #50051),HDAC2 (BPS Bioscience, #50053), or HDAC3/NcoR2 (BPS Bioscience, #50003)at concentrations of 1.25, 1.32, and 0.167 μg/mL, respectively.Following pre-incubation, Fluor-de-Lys™ substrate (Enzo Life Sciences,Plymouth Meeting, Pa., BML-KI104-0050) was added to a finalconcentration of 10 μM and plates were further incubated for 30 minutesat room temperature. The enzymatic reaction was stopped by addition ofTrichostatin A (Sigma-Aldrich, St Louis, Mo., #T8552, finalconcentration: 100 nM) and trypsin (MP Biomedicals, Solon, Ohio,#02101179) was added to reach a final concentration of 100 μg/mL. Aftera 15 minute incubation at room temperature, fluorescence was recordedusing a Spectramax M2 fluorometer (Molecular Devices, Sunnyvale, Calif.)with excitation at 365 nm and emission at 460 nm. IC50 values werecalculated by using a sigmoidal dose-response (variable slope) equationin GraphPad Prism® 5 for Windows (GraphPad Software, La Jolla, Calif.).Results for selected compounds in the HDAC activity inhibition assay arepresented in Table 5 (IC₅₀ ranges: IA>20 μM, A<1 μM, 1<B<5 μM, 5<C<10μM, 10<D<20 μM, ND: not determined).

Acid Stability Determination

A 100 μM solution of test compound was prepared by dilution of a 10 mMDMSO stock solution in a 0.01 M solution of HCl in deionized water.Immediately after mixing, an aliquot (100 μL) was sampled and analyzedby HPLC/UV. The area under the compound peak was determined and used asthe time zero reference point. The remainder of the acid sample wasincubated at 50° C. and samples were taken after 2, 4, and 24 hours ofincubation. On a few occasions, samples were taken at 30 rather than 24hours. These were analyzed by the same HPLC/UV method and the area ofthe peak corresponding to the test compound was measured. Percentremaining at a given time point was then calculated as the ratio of thearea under the peak after incubation to that at time zero times 100. Inthose cases where a 30 hour time point was recorded, the percentremaining at 24 hours was obtained by interpolation of the percentremaining versus time curve assuming a unimolecular process, i.e. amonoexponential decay. Percent remaining after 24 hours incubation arepresented in Table 5 below, where A corresponds to more than 60%, B isbetween 40 and 60%, C covers 20 to 40% and D means less than 20%.

Brain Penetration Studies

Test compounds were prepared at either 0.5 mg/ml or 5 mg/ml in 30%hydroxypropyl-β-cyclodextrin, 100 mM sodium acetate pH 5.5, 5% DMSO.C57/BL6/J mice were dosed s.c. at 5 mg/kg or 50 mg/kg, or i.v. at 5mg/kg. Animals were euthanized at pre-dose, 5, 15, 30 min, 1, 2 and 4hours post-dose and plasma and brain obtained. Three animals per doseper time points were used. The levels of compound in the plasma andbrain were determined by standard LC/MS/MS methods. Brain/plasma ratio(BPR) was calculated as the ratio of the C_(max)(brain)/C_(max)(plasma).The results are shown in Table 5, where IA corresponds to a BPR lessthan 0.1, D is between 0.1 and 0.2, C is 0.2 to 0.5, B comprises 0.5 to1 and A is greater than 1.

In-Cell Deacetylase Inhibition Assay (DAC Assay)

GM 15850(lymphoblastoid cells line) cells were seeded in 96-well platesat an appropriate density (100,000 cells/well) in 90 μL RPMI1640 mediumcontaining 10% v/v fetal bovine serum (FBS), 1% v/vpenicillin/streptomycin, and 1% v/v L-glutamine. Compound dilutions weremade in 100% DMSO followed by parallel dilution in media with 2% DMSO.10 μl of the compound dilutions were added to the cells to achieve thedesired concentrations. The final concentration of DMSO in each well was0.2%. The cells were incubated for 4 h at 37° C. with 5% CO₂. Afterincubation, the cells were centrifuged down and the supernatant wasremoved. The cell pellets were washed with 100 μL phosphate-bufferedsaline (PBS) and then lysed with 45 μL lysis buffer (HDAC assay bufferat pH 8.0 (25 mM Tris/HCl, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl₂)+1% v/vIgepal CA-630). To initiate the reaction, the HDAC substrate KI-104(Enzo Life Sciences, Farmingdale, N.Y.) was added to a finalconcentration of 50 μM. The reaction was stopped after 30 min incubationby addition of 50 μL developer (6 mg/mL trypsin in HDAC assay buffer).The reaction was allowed to develop for 30 min at room temperature andthe fluorescence signal was detected using a fluorometer (Spectramax M2,Molecular Devices, Sunnyvale, Calif.) with excitation and emissionwavelengths of 360 nm and 470 nm respectively. The data was fitted to asigmoidal dose response equation with variable slope in GraphPad Prism5.0 (GraphPad Software, La Jolla, Calif.) to determine IC50. Bottom andtop of the curve were fixed to the average fluorescence response ofcontrol wells with no cells and cells but no compound respectively.IC50's are reported in Table 5, where A stands for IC50 less than 1 μM,B between 1 and 5 μM, C from 5 to 10 μM, D from 10 to 20 μM, and IA forIC50 above 20 μM.

Effect of HDAC Inhibitors on Frataxin (FXN) mRNA Expression

Blood is collected from Friedreich's ataxia patient donors into tubescontaining the anti-coagulant EDTA. Primary lymphocytes are isolatedusing Lymphocyte Separation Medium (MP Biomedicals, Solon, Ohio)following the manufacturer's instructions and including a fewmodifications made by Repligen. After a final wash in Phosphate BufferedSaline (PBS), the cells are distributed into a 6-well cell culture platein cell growth medium. The test HDAC inhibitor compound is added tocells in a dose escalating manner (usually concentrations range from 1to 10 μM) and 0.1% DMSO is added to one well of cells as a no treatmentcontrol. Cells are incubated for 48 hours at 37° C. in a CO₂ incubator;cell counts are taken using a Countess automated cell counter(Invitrogen, Carlsbad, Calif.). Equivalent numbers of cells for alltreatment conditions are pelleted by centrifugation and resuspended incell lysis buffer. Total RNA is isolated from approximately 1×10⁶primary lymphocytes using a RNeasy Mini Kit (Qiagen, Valencia, Calif.),following the manufacturer's instructions and including an optionalon-column DNAse digestion step. The isolation is performed eithermanually or using the QIAcube (Qiagen, Valencia, Calif.), an instrumentthat automates much of the isolation procedure. The RNA yield andconcentration is determined using a Nanodrop spectrophotometer (ThermoFisher Scientific, Waltham, Mass.) and depending on the RNAconcentration, one of two protocols is used to measure frataxin (FXN)transcript levels. For samples containing at least 15 ng/μL RNA aTaqMan® Probe-based (Applied Biosystems, Carlsbad, Calif.) qRT-PCRmethod is used, while for samples containing less than 15 ng/μL RNA aSYBR Green qRT-PCR method is used. In the TaqMan® Probe-based methodspecific primer/probe pairs for FXN and GAPDH are multi-plexed in eachreaction. In the SYBR Green method FXN and GAPDH are amplified inseparate reactions. In both methods each RNA sample is analyzed intriplicate (preferably) or duplicate (minimally) using a one-stepqRT-PCR master mix that contains all the components necessary for cDNAsynthesis and PCR amplification in a single, continuous reaction. Aftercycling is complete, MxPro Software (Agilent Technologies, Santa Clara,Calif.) is used to analyze the collected data and determine the relativeamount of FXN mRNA compared to a control sample. An adaptive baselinemethod is used for baseline correction whereby an algorithmautomatically selects the appropriate baseline cycles for each well andeach dye. An amplification-based threshold is set and the correspondingthreshold cycle, or Ct, is obtained for calculating targetconcentration. The Ct values for each target gene (FXN and GAPDH) foreach replicate series are averaged. The amount of FXN (or GAPDH) in thesample is determined as the relative quantity to the calibrator wherethe calibrator sample is assigned an arbitrary quantity of 1. Thefollowing equation is used: Relative quantity to the calibrator=2^(−Δct)where ΔCt=(Ct_gene)unknown−(Ct_gene)calibrator , gene is either FXN orGAPDH, calibrator is a DMSO control sample, and unknown is a HDACitreated sample. The relative quantity of FXN is normalized to cellnumber and RNA input. Data is reported in Table 5 below, where theconcentration required for a 2-fold increase in FXN mRNA is reported asA if less than 5 μM, B if between 5 and 10 μM, C if greater than 10 μM.

Hepatocyte Protocol

To assess the stability and metabolism of RGFP compounds and to quantifythe metabolites in hepatocytes. This assay was designed to evaluate themetabolism of RGFP compounds, following their incubation with human,monkey, dog and rat hepatocytes by monitoring either parent drugdisappearance or metabolite appearance using LC-MS/MS. The results areshown in Table 5 ((% Left in Hep: IA<10%, 50%<A, 50%>B>30%, 30%>C>10%,ND: not determined).

Equipment

Applied Biosystem Triple Quadrupole LC/MS/MS; Ice bucker, timer; 96 wellplates; Falcon, Cat #353072; 96 well plates shaker; Various pipettes: 10μL, 20 μL, 200 μL, and 1000 μL; Test tubes: Catalog #VWR 47729-572,13×100 mm

TABLE 3 Materials and Reagents Item Vendor Catalog # Human HepatocytesCelsis X008001 Monkey Hepatocytes Celsis M00350 Dog Hepatocytes CelsisM00205 Rat Hepatocytes Celsis M00005 Torpedo Antibiotix Mix InvitroTechnologies Z99000 In VitroGRO HT Medium Celsis Z99019 In VitroGRO KHBCelsis Z99074 Acetonitrile Fisher A-9981 Methanol Fisher A-4521 TrypanBlue Solution Sigma Chemical T-8154

Procedure: Turn on the water-bath heater to 37° C. Take out the KHBbuffer and make sure it is at room temp before use. Prepare 2.5 mMconcentration of RGFP compound in DMSO stock. Add 10 μL of above DMSOstock to 2490 μL KHB buffer; final concentration of RGFP compound willbe 10 μM. Pre-warm 45 ml InVitro HT Medium to 37° C. in a sterile 50 mlconical tube. Add 1.0 mL Torpedo Antibiotic Mix per 45 mL InVitro HTmedium. Transfer 13 mL of warm HT medium with Antibiotic Mix into a 15mL conical tube. Carefully remove the hepatocyte vials from liquidnitrogen (liquid phase). Immediately immerse the vial into a 37° C.water bath. Shake gently until the ice melts entirely. Do not keep thecells in 37° C. water bath longer than necessary. Immediately emptycontents of the vial into 13 ml of pre-warmed InVitro HT Medium withantibiotics. Rinse the vial with the HT media just transferred thehepatocytes to, in order to ensure complete transfer. Centrifuge thecell suspension at 600 RPM for 5 minutes at room temperature. Discardthe supernatant by either pouring in one motion (do not pour partiallyand re-invert centrifuge tube) or aspirating using a vacuum pump. Add1.0 ml of KHB (at room temperature) buffer to the tube of hepatocytepellet. Loosen the cell pellet by gently swirling the centrifuge tube.Transfer 100 μL of above solution to a different tube and add 900 μL ofKHB buffer to count the cells. Determine the total cell count and thenumber of viable cells using the Trypan Blue exclusion method. Once thecell count is obtained, multiply the number by 10 (attributing to thedilution factor). Add required volume of KHB buffer to the tubecontaining hepatocytes such that the final count will be 2 millioncells/mL. Dispense 50 μL of 2 million cells/ml to a 96 well plate andthen add 50 μl of DMSO stock to respective wells (such that, theconcentration of RGFP compounds is 5 μM and number of cells are 100000in each well). Place the plates on a shaker in a 37° C. incubator with5% CO₂. Separate plates for each time point are advisable (Time points:0 h, 1 h, 2 h, and 6 h). After each time point, add 100 μL of quenchingsolution. Quenching solution is an acetonitrile solution containingRGFP531 (10 μM) internal standard, 0.1% formic acid and phenylglyoxol(400 μM). The formic acid and phenylglyoxal is used for theidentification and quantification of OPD as mentioned above. Pipette upand down a few times to ensure a complete stop of reaction. Transfer allthe solution into a 1.5 ml tube, vortex thoroughly, and centrifuge at14000 RPM at 4° C. for 5 minutes to precipitate cell debris. Transferthe 150 μL of supernatant to vials for analysis on LC-MS/MS.

LC-MS/MS parameters for RGFP compounds and metabolites including OPD:LC-MS/MS Parameters for API 2000 QTrap: System: HPLC 1100; Column:Gemini C18, 5 μM 4.6×50 mm; Column Temp: Ambient; MS: API 2000 QTrap (MImode); Mobile Phase A: HPLC water with 0.05% Formic Acid; Mobile PhaseB: Acetonitrile with 0.05% Formic Acid. Table 4 shows an exemplary HPLCmethod for compound A11, which can be modified for other compounds asdisclosed herein.

TABLE 4 HPLC method for 2000QTrap LCMS Total time Flow Rate (min)(ul/min) A % B % C % D % 0 750 85 15 0 0 0.5 750 85 15 0 0 2.5 750 5 950 0 5 750 5 95 0 0 5.5 750 85 15 0 0 7.5 750 85 15 0 0

TABLE 5 Cmax DAC % left Fxn HDAC1 HDAC2 HDAC3 brain IC50 6 h Hum acidformed OPD >2X Acid Stability Coding Structure MW clogP tPSA IC50 (uM)IC50 (uM) IC50 (uM) BPR (ng/mL) (uM) hep (absolute) (ng/mL) uM % Left 24hr A1 

A 1.51 83 A A A C C A A No acid No OPD ND ND A2 

A 3.01 71 A A A A C A B No acid No OPD ND B A3 

A 1.12 86 A A A C C A A A No OPD ND ND A4 

A 1.74 83 A A C C A A No acid No OPD ND ND A5 

A 2.51 83 A A A C C A B No acid No OPD ND ND A6 

A 1.86 83 A A A ND ND B B No acid No OPD ND A A7 

A 2.08 83 A A A C C B B No Acid No OPD ND B A8 

A 2.85 83 A B A ND ND B A No Acid No OPD ND A A9 

A 3.22 71 A A A A C ND B No Acid No OPD A A A10

A 3.57 71 A A A A B ND C No Acid No OPD ND C A11

A 2.21 71 A A A C B ND B No Acid No OPD ND B A12

A 2.56 71 B C A B B IA C No Acid No OPD C B A13

A 1.51 83 A A A IA C A A A No OPD ND ND A14

A 1.74 83 A A C C A A A No OPD ND ND A15

A 2.51 83 A B A IA C A A A No OPD ND ND

REFERENCES

-   1) 2012. o-Phenylenediamine [MAK Value Documentation, 1999]. The MAK    Collection for Occupational Health and Safety. 216-235.-   2) A Comprehensive Guide to the Hazardous Properties of Chemical    Substances by Pradyot Patnaik, 3rd edition, Pg 257-258.-   3) Weisburger E K, Russfield A B, Homburger F, Weisburger J H, Boger    E, Van Dongen C G, Chu K C (1978) Testing of twenty-one    environmental aromatic amines or derivatives for long-term toxicity    or carcinogenicity. J Environ Pathol Toxicol 2: 325-356.-   4) Sontag J M (1981) Carcinogenicity of substituted-benzenediamines    (phenylenediamines) in rats and mice. J Nat Cancer Inst 66: 591-601.-   5) Bioassay of 4-Chloro-o-phenylenediamine for possible    caricogeneicty. National Cancer Institute CARCINOGENESIS Technical    Report Series No. 63, 1978.-   6) Saruta N, Yamaguchi S, Matsuoka T (1962) Sarcoma produced by    subdermal administration of metaphenylenediamine and    metaphenylenediamine hydrochloride. Kyushu J Med Sci, 13: 175-179.

A number of embodiments have been described herein. Nevertheless, itwill be understood that various modifications may be made withoutdeparting from the spirit and scope of the disclosure. Accordingly,other embodiments are within the scope of the following claims.

What is claimed:
 1. A compound having formula (I), or a pharmaceuticallyacceptable salt thereof:

wherein: R₁—X is attached to only one of the ring nitrogen atoms; X is:(i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; (ii) direct bond; or (iii)C═O, C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k), NR^(k)—SO₂,C(═O)NR^(k) or NR^(k)—C(═O); wherein: Y is bond, CR^(c)═CR^(d), O,NR^(c), or S(O)_(m); each of A and B is, independently, a bond, O,NR^(f), or S(O)_(m); a is 1, 2, or 3; b is0, 1, 2, or3; m is 0, 1, or 2;each occurrence of R^(a) and R^(b) is independently selected from H, F,OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or one or moreof the following can apply with respect to R^(a) and R^(b): any twoR^(a) , together with the carbons to which each is attached, togetherform C3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in whichone of the heterocyclyl ring atoms is selected from O, S(O)_(m) andNR^(g); or one R^(a) and one R^(b), together with the carbons to whicheach is attached, form C3-C6 cycloalkyl or heterocyclyl including 3-6ring atoms, in which one of the heterocyclyl ring atoms is selected fromO; S(O)m and NR^(g); or any two R^(b), together with the carbons towhich each is attached, form C3-C6 cycloalkyl or heterocyclyl including3-6 ring atoms, in which one of the ring atoms is selected from O; S(O)mand NR^(g); each of R^(c) and R^(d) is independently selected from H, F,OH, C1-C6 alkyl, C3-C5 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C5cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; or R^(c) andR^(d), together with the carbons to which each is attached form a C5-C7cycloalkyl or heterocyclyl including 3-6 ring atoms, in which from 1-2of the heterocyclyl ring atoms are independently selected from O,S(O)_(m) and NR^(g); each occurrence of R^(c), R^(f), R^(g) and R^(g′)is independently selected from H, C1-C6 alkyl, —C(═O)H, —C(═O)R^(h),C(═O)O(C1-C6 alkyl), C(═O)N(R^(i))₂, and SO₂—R^(h); wherein R^(h) isselected from C1-C6 alkyl, CH₂-(heteroaryl including 5-10 ring atoms),CH₂—(C6-C10 aryl), and C6-C10 aryl; and each occurrence of R^(i) isindependently selected from H, C1-C6 alkyl, CH₂-(heteroaryl including5-10 ring atoms), CH₂—(C6-C10 aryl), and C6-C10 aryl; each occurrence ofR^(j) is independently selected from H, F, OH, C1-C6 alkyl, C3-C6cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6alkoxy, C1-C6 fluoroalkoxy, and cyano; or R^(j)—C—R^(j) together formC3-C6 cycloalkyl or heterocyclyl including 3-6 ring atoms, in which oneof the heterocyclyl ring atoms is selected from O; S(O)m and NR^(j′);each occurrence of R^(j′) and R^(k) is independently selected from H,C1-C6 alkyl, —C(═O)H, —C(═O)R^(m), C(═O)O(C1-C6 alkyl), C(═O)N(R^(n))₂,and SO₂—R^(m), wherein R^(m) is selected from C1-C6 alkyl,CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10 aryl), andC6-C10 aryl; and each occurrence of R^(n) is independently selected fromH, C1-C6 alkyl, CH₂-(heteroaryl including 5-10 ring atoms), CH₂—(C6-C10aryl), and C6-C10 aryl, and wherein the aryl and heteroaryl portion inR^(m) and R^(n) can be optionally substituted with 1-3 independentlyselected substituents F, C1-C6 alkyl, fluoro C1-C6 alkyl, C3-C6cycloalkyl, C1-C6 alkoxy, C1-C6 fluoroalkoxy, or cyano; further wherein:(a) when each of A and B is a bond, and b is 0, then X has the followingformula: —Y—[C(R^(a))₂]_(a)—; (b) when b is 0 or 1, then A and B cannotboth be heteroatoms; and (c) when A or B serves as the point ofconnection of X to the nitrogen ring atoms, then A or B cannot be aheteroatom; R1 is: (i) monocyclic or bicyclic heteroaryl including from5-10 ring atoms, which is optionally substituted with from 1-3 R^(o);wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o), and S; (ii) C6-C10 aryl, which isoptionally substituted with from 1-3 R^(o); or (iii) C3-C10 cycloalkylor C3-C10 cycloalkenyl, each of which is optionally substituted withfrom 1-6 R^(o); (iv) heterocyclyl including from 3-10 ring atoms, whichis optionally substituted with from 1-6 R^(o); wherein from 1-4 of thering atoms are a heteroatom independently selected from O, N, N—H,N—R^(o), and S; (v) hydrogen; R4 is H or R^(o) and each occurrence ofR^(o) is independently selected from the group consisting of halogen;C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—;(C1-C6 alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together form asaturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms areoptionally a heteroatom independently selected from NH, N(C1-C6alkyl),O, or S; formyl; formyl(C₁-C₄) alkyl; cyano; cyano(C₁-C₄) alkyl; benzyl;benzyloxy; (heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclylportion includes 5 or 6 ring atoms, in which 1 or 2 of the ring atomsare a heteroatom independently selected from NH, N(alkyl), O, or S, andwhen said alkyl portion is present, said alkyl portion serves as thepoint of attachment to R, and when the alkyl portion is not present, aheterocyclyl carbon ring atom serves as the point of attachment of theheterocyclyl to R1; phenyl; heteroaryl including from 5-6 ring atoms,wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o″), and S, each of which is optionallysubstituted with from 1-3 R^(o″); SO₂—(C1-C6)alkyl; SO—(C1-C6)alkyl; andnitro; each occurrence of R^(o″) is independently selected from thegroup consisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl;hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; formyl; formyl(C₁-C₄)alkyl; cyano; cyano(C₁-C₄) alkyl; benzyl; benzyloxy;(heterocyclyl)-(C0-C6) alkyl, wherein the heterocyclyl portion includes5 or 6 ring atoms, in which 1 or 2 of the ring atoms are a heteroatomindependently selected from NH, N(C1-C6alkyl), O, or S, and when saidalkyl portion is present, said alkyl portion serves as the point ofattachment to R1; and when the alkyl portion is not present, aheterocyclyl carbon ring atom serves as the point of attachment of theheterocyclyl to R1; phenyl; heteroaryl including from 5-6 ring atoms,wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—(C1-C6 alkyl), and S; SO₂—(C1-C6)alkyl ;SO—(C1-C6)alkyl ; and nitro; R5 is selected from the group consistingof: hydrogen, halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl;hydroxy(C₁-C₄)alkyl; (C1-C6 alkyl)C(O)—; formyl; formyl(C₁-C₄) alkyl;cyano; cyano(C₁-C₄) alkyl; benzyl; (heterocyclyl)-(C0-C6)alkyl, whereinthe heterocyclyl portion includes 5 or 6 ring atoms, in which 1 or 2 ofthe ring atoms are a heteroatom independently selected from NH,N(C1-C6alkyl), O, or S, and when said alkyl portion is present, saidalkyl portion serves as the point of attachment to R1; and when thealkyl portion is not present, a heterocyclyl carbon ring atom serves asthe point of attachment of the heterocyclyl to R1; phenyl; heteroarylincluding from 5-6 ring atoms, wherein from 1-4 of the ring atoms are aheteroatom independently selected from O, N, N—H, N—R^(q″), and S, eachof which is optionally substituted with from 1-3 R^(q″);SO₂—(C1-C6)alkyl; SO—(C1-C6)alkyl and nitro; R2 is selected from H, F,Cl, CF₃, CF₂CF₃, CH₂CF₃, OCF₃, OCHF₂, phenyl; or phenyl substituted with1-3 R^(o); and R3 is H, F, or Cl.
 2. The compound or salt of claim 1,wherein the compound or salt has formula (Ia):


3. The compound or salt of claim 1, wherein the compound or salt hasformula (Ib):


4. The compound or salt of any one of claims 1-3, wherein X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—.
 5. The compound or salt ofclaim 4, wherein A is a bond, B is a bond, or both A and B are each abond.
 6. The compound or salt of claim 4 or 5, wherein each occurrenceof R^(a) and R^(b) is independently selected from H, F, OH, C1-C6 alkyl,C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6alkoxy, C1-C6 fluoroalkoxy, and cyano.
 7. The compound or salt accordingto any one of claims 4-6, wherein each occurrence of R^(a) and R^(b) isindependently selected from H, F, C1-C6 alkyl, and C3-C6 cycloalkyl. 8.The compound or salt according to any one of claims 4-7, wherein eachoccurrence of R^(a) and R^(b) is H.
 9. The compound or salt of claim 4,wherein Y is a bond.
 10. The compound or salt according to claim 9,wherein A is a bond, O, or NR^(c).
 11. The compound or salt according toclaim 9 or 10, wherein A is a bond.
 12. The compound or salt accordingto any one of claims 9-11, wherein each occurrence of R^(a) and R^(b) isindependently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl,NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6fluoroalkoxy, and cyano.
 13. The compound or salt according to any oneof claims 9-12, wherein each occurrence of R^(a) and R^(b) isindependently selected from H, F, C1-C6 alkyl, and C3-C6 cycloalkyl. 14.The compound or salt according to any one of any one of claims 9-13,wherein each occurrence of R^(a) and R^(b) is H.
 15. The compound orsalt according to any one of claims 9-14, wherein a is
 1. 16. Thecompound or salt according to any one of claims 9-15, wherein b is 0.17. The compound or salt according to any one of claims 9-16, wherein Xis CH₂.
 18. The compound or salt according to any one of claims 9-15,wherein b is 1, 2, or
 3. 19. The compound or salt according to any oneof claims 9-15 and 18, wherein X is (CH₂)₂₋₄.
 20. The compound or saltof claim 4, wherein Y is CR^(c)═CR^(d).
 21. The compound or salt ofclaim 20, wherein the double bond between CR^(c) and CR^(d) has thetrans configuration.
 22. The compound or salt of claim 20 or 21, whereineach of R^(c) and R^(d) is H.
 23. The compound or salt according to anyone of claims 20-22, wherein A is a bond, B is a bond, or each of A andB is a bond.
 24. The compound or salt according to any one of claims20-23, wherein each occurrence of R^(a) and R^(b) is independentlyselected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, andcyano.
 25. The compound or salt according to any one of claims 20-24,wherein each occurrence of R^(a) and R^(b) is independently selectedfrom H, F, C1-C6 alkyl, and C3-C6 cycloalkyl.
 26. The compound or saltaccording to any one of claims 20-25, wherein each occurrence of R^(a)and R^(b) is H.
 27. The compound or salt according to any one of claims20-26, wherein one or both of the following apply: (i) a is 1 or 2, and(ii) b is 0 or
 1. 28. The compound or salt according to any one ofclaims 20-27, wherein b is
 0. 29. The compound or salt according to anyone of claims 20-28, wherein X is —CH═CH—C(R^(a))₂— or—CH═CHC(R^(a))₂C(R^(a))₂—.
 30. The compound or salt of claim 4, whereinY is O.
 31. The compound or salt of claim 4, wherein Y is NR^(c). 32.The compound or salt according to claim 30 or 31, wherein A is a bond, Bis a bond, or each of A and B is a bond.
 33. The compound or saltaccording to any one of claims 30-32, wherein each occurrence of R^(a)and R^(b) is independently selected from H, F, OH, C1-C6 alkyl, C3-C6cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6alkoxy, C1-C6 fluoroalkoxy, and cyano.
 34. The compound or saltaccording to any one of claims 30-33, wherein each occurrence of R^(a)and R^(b) is independently selected from H, F, C1-C6 alkyl, and C3-C6cycloalkyl.
 35. The compound or salt according to any one of claims30-34, wherein each occurrence of R^(a) and R^(b) is H.
 36. The compoundor salt according to any one of claims 30-35, wherein a is 2 or 3 and bis optionally other than
 0. 37. The compound or salt according to anyone of claims 30-36, wherein X is —O—(CH₂)₂₋₃ or —N(CH₃)—(CH₂)₂₋₃. 38.The compound or salt according to any one of claims 4, 5, 9-11 15, 16,18, 20-23, 27, 28, and 30-32, wherein one or more of the followingapply: any two R^(a), together with the carbons to which each isattached, together form C3-C6 cycloalkyl or heterocyclyl including 3-6ring atoms, in which one of the heterocyclyl ring atoms is selected fromO, S(O)_(m) and NR^(g); or one R^(a) and one R^(b), together with thecarbons to which each is attached, form C3-C6 cycloalkyl or heterocyclylincluding 3-6 ring atoms, in which one of the heterocyclyl ring atoms isselected from O, S(O)_(m) and NR^(g); or any two R^(b), together withthe carbons to which each is attached, form C3-C6 cycloalkyl orheterocyclyl including 3-6 ring atoms, in which one of the ring atoms isselected from O, S(O)_(m) and NR^(g).
 39. The compound or salt accordingto any one of claims 1-3, wherein X is a bond.
 40. The compound or saltaccording to any one of claims 1-39, wherein R1 is C3-C10 cycloalkyl orC3-C10 cycloalkenyl, each of which is optionally substituted with from1-3 R^(o).
 41. The compound or salt according to any one of claims 1-40,wherein R1 is C3-C10 cycloalkyl, which is optionally substituted withfrom 1-3 R^(o).
 42. The compound or salt according to any one of claims1-41, wherein R1 is C3-C6 cycloalkyl, which is optionally substitutedwith from 1-3 R^(o).
 43. The compound or salt according to any one ofclaims 1-42, wherein R1 is cyclopropyl, which is optionally substitutedwith from 1-3 R^(o).
 44. The compound or salt according to any one ofclaims 1-43, wherein R1 is unsubstituted C3-C6 cycloalkyl.
 45. Thecompound or salt according to any one of claims 1-44, wherein R1 isunsubstituted cyclopropyl.
 46. The compound or salt according to any oneof claims 1-39, wherein R1 is C6-C10 aryl, which is optionallysubstituted with from 1-3 R^(o).
 47. The compound or salt according toany one of claims 1-39 and 46, wherein R1 is phenyl or naphthyl, whichis optionally substituted with from 1-3 R^(o).
 48. The compound or saltaccording to any one of claims 1-39 and 46, wherein R1 is C8-C10 aryl,which contains a phenyl ring fused to a non-aromatic ring and which isoptionally substituted with from 1-3 R^(o).
 49. The compound or saltaccording to any one of claims 1-39, wherein R1 is monocyclic orbicyclic heteroaryl including from 5-10 ring atoms, which is optionallysubstituted with from 1-3 R^(o); wherein from 1-4 of the ring atoms area heteroatom independently selected from O, N, N—H, N—R^(o), and S. 50.The compound or salt according to any one of claims 1-39, wherein R1 ismonocyclic heteroaryl including from 5-6 ring atoms, which is optionallysubstituted with from 1-3 R^(o); wherein from 1-4 of the ring atoms area heteroatom independently selected from O, N, N—H, N—R^(o), and S. 51.The compound or salt according to any one of claims 1-39 and 49, whereinR1 is bicyclic heteroaryl including from 8-10 ring atoms, which isoptionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S.
 52. The compound or salt according to any one of claims 1-39,wherein R1 is heterocyclyl including from 3-10 ring atoms, which isoptionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S.
 53. The compound or salt according to any one of claims 1-39,wherein R1 is H.
 54. The compound or salt according to any one of claims1-53, wherein R4 is H or halo.
 55. The compound or salt according to anyone of claims 1-54, wherein R4 is H.
 56. The compound or salt accordingto any one of claims 1-55, wherein R5 is H.
 57. The compound or saltaccording to any one of claims 1-56, wherein R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 58. The compound or salt according toany one of claims 1-56, wherein R2 is hydrogen, and R3 is F or Cl. 59.The compound or salt according to any one of claims 1-56 and 58, whereinR2 is hydrogen, and R3 is fluoro.
 60. The compound or salt according toany one of claims 1-56, wherein each of R2 and R3 is hydrogen.
 61. Thecompound or salt according to any one of claims 1-60, wherein each R^(o)is independently selected from the group consisting of halogen; C1-C6alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R⁴⁰ together form a saturatedring having 5 or 6 ring atoms, in which 1 or 2 ring atoms are optionallya heteroatom independently selected from NH, N(C1-C6alkyl), O, or S;cyano; phenyl; heteroaryl including from 5-6 ring atoms, wherein from1-4 of the ring atoms are a heteroatom independently selected from O, N,N—H, N—R^(o″), and S, each of which is optionally substituted with from1-3 R^(o″); and SO₂—(C1-C6)alkyl.
 62. The compound or salt according toany one of claims 1-61, wherein each R^(o) is independently selectedfrom the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; and SO₂—(C 1-C6)alkyl.
 63. Thecompound or salt according to any one of claims 1-62, wherein each R^(o)is independently selected from the group consisting of halogen, C1-C6alkyl, and fluoro(C1-C6)alkyl.
 64. The compound or salt according to anyone of claims 1-63, wherein: X is: (i)—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; (ii) direct bond; or (iii) C═O,C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k), NR^(k)—SO₂, C(═O)NR^(k) orNR^(k)—C(═O); R1 is: (i) monocyclic or bicyclic heteroaryl includingfrom 5-10 ring atoms, which is optionally substituted with from 1-3R^(o); wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o), and S; (ii) C6-C10 aryl, which isoptionally substituted with from 1-3 R^(o); (iii) C3-C10 cycloalkyl orC3-C10 cycloalkenyl, each of which is optionally substituted with from1-3 R^(o); (iv) heterocyclyl including from 3-10 ring atoms, which isoptionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from 0, N, N—H, N—R^(o),and S; or (v) hydrogen; R^(o) is independently selected from the groupconsisting of halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl;hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; —N*(R^(o′))₂, whereinR^(o′)—N*—R^(o′) together form a saturated ring having 5 or 6 ringatoms, in which 1 or 2 ring atoms are optionally a heteroatomindependently selected from NH, N(C1-C6alkyl), O, or S; cyano; phenyl;heteroaryl including from 5-6 ring atoms, wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o″),and S, each of which is optionally substituted with from 1-3 R^(o″); andSO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 65.The compound or salt according to any one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is: (i) monocyclic orbicyclic heteroaryl including from 5-10 ring atoms, which is optionallysubstituted with from 1-3 R^(o); wherein from 1-4 of the ring atoms area heteroatom independently selected from O, N, N—H, N—R^(o), and S; (ii)C6-C10 aryl, which is optionally substituted with from 1-3 R^(o); or(iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, each of which isoptionally substituted with from 1-3 R^(o); (iv) heterocyclyl includingfrom 3-10 ring atoms, which is optionally substituted with from 1-3R^(o); wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o), and S; or (v) hydrogen; R^(o) isindependently selected from the group consisting of halogen; C1-C6alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together form asaturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms areoptionally a heteroatom independently selected from NH, N(C1-C6alkyl),O, or S; cyano; phenyl; heteroaryl including from 5-6 ring atoms,wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o″), and S, each of which is optionallysubstituted with from 1-3 R^(o″); and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 66. The compound or salt according toany one claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond; R1 is: (i)monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, whichis optionally substituted with from 1-3 R^(o); wherein from 1-4 of thering atoms are a heteroatom independently selected from O, N, N—H,N—R^(o), and S; (ii) C6-C10 aryl, which is optionally substituted withfrom 1-3 R^(o); or (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, eachof which is optionally substituted with from 1-3 R^(o); (iv)heterocyclyl including from 3-10 ring atoms, which is optionallysubstituted with from 1-3 R^(o); wherein from 1-4 of the ring atoms area heteroatom independently selected from O, N, N—H, N—R^(o), and S; or(v) hydrogen; R^(o) is independently selected from the group consistingof halogen, C1-C6 alkyl, and fluoro(C1-C6)alkyl; R4 is hydrogen or halo;R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii) R2 ishydrogen, and R3 is fluoro; or (iii) R2 is a substituent other thanhydrogen, and R3 is hydrogen.
 67. The compound or salt according to anyone of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(_(Rb))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; R1 is: (i)monocyclic or bicyclic heteroaryl including from 5-10 ring atoms, whichis optionally substituted with from 1-3 R^(o); wherein from 1-4 of thering atoms are a heteroatom independently selected from O, N, N—H,N—R^(o), and S; (ii) C6-C10 aryl, which is optionally substituted withfrom 1-3 R^(o); or (iii) C3-C10 cycloalkyl or C3-C10 cycloalkenyl, eachof which is optionally substituted with from 1-3 R^(o); (iv)heterocyclyl including from 3-10 ring atoms, which is optionallysubstituted with from 1-3 R^(o); wherein from 1-4 of the ring atoms area heteroatom independently selected from O, N, N—H, N—R^(o), and S; or(v) hydrogen; R^(o) is independently selected from the group consistingof halogen, C1-C6 alkyl, and fluoro(C1-C6)alkyl; R4 is hydrogen or halo;R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii) R2 ishydrogen, and R3 is fluoro; or (iii) R2 is a substituent other thanhydrogen, and R3 is hydrogen.
 68. The compound or salt according to anyone claims 1-63, wherein: X is: (i)—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; (ii) direct bond; or (iii) C═O,C(R^(j))₂—C(═O), or C(═O)—C(R^(j))₂, SO₂—NR^(k), NR^(k)—SO₂, C(═O)NR^(k)and NR^(k)—C(═O); R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl,optionally substituted with from 1-3 R^(o); R^(o) is independentlyselected from the group consisting of halogen, C1-C6 alkyl, andfluoro(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 69.The compound or salt according to any one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is C3-C10cycloalkyl orC3-C10cycloalkenyl, optionally substituted with from 1-3 R^(o); R^(o) isindependently selected from the group consisting of halogen; C1-C6alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)C(O)—; (C1-C6 alkyl)NH—; (C1-C6alkyl)₂N—; —N*(R^(o′))₂, wherein R^(o′)—N*—R^(o′) together form asaturated ring having 5 or 6 ring atoms, in which 1 or 2 ring atoms areoptionally a heteroatom independently selected from NH, N(C1-C6alkyl),O, or S; cyano; phenyl; heteroaryl including from 5-6 ring atoms,wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o″), and S, each of which is optionallysubstituted with from 1-3 R^(o″); and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 70. The compound or salt according toany one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is C3-C10 cycloalkyl orC3-C10 cycloalkenyl, optionally substituted with from 1-3 R^(o); R^(o)is independently selected from the group consisting of: halogen; C1-C6alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; andSO₂—(C1-C6)alkyl.; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 71.The compound or salt according to any one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond; R1 is C3-C10cycloalkyl or C3-C10 cycloalkenyl, optionally substituted with from 1-3R^(o); R^(o) is independently selected from the group consisting ofhalogen, C1-C6 alkyl, and fluoro(C1-C6)alkyl; R4 is hydrogen or halo; R5is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii) R2 ishydrogen, and R3 is fluoro; or (iii) R2 is a substituent other thanhydrogen, and R3 is hydrogen.
 72. The compound or salt according to anyone of claims 1-63, wherein: X is —Y—[C(R^(a))₂]_(a)-A-[C(_(R)^(b))₂]_(b)—B—, Y is a bond, and each occurrence of R^(a) and R^(b) isindependently selected from H, F, OH, C1-C6 alkyl, C3-C6 cycloalkyl,NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6 cycloalkyl), C1-C6 alkoxy, C1-C6fluoroalkoxy, and cyano; R1 is C3-C10 cycloalkyl or C3-C10 cycloalkenyl,optionally substituted with from 1-3 R^(o); R^(o) is independentlyselected from the group consisting of: halogen; C1-C6 alkyl;fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N−; cyano; andSO₂—(C1-C6)alkyl ; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 73.The compound or salt according to any one of claims 1-63, wherein: X is:(i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; (ii) direct bond; or (iii)C═O, C(R^(j))₂—C(═O), or C(═O)—C(R^(j))₂, SO₂—NR^(k), NR^(k)—SO₂,C(═O)NR^(k) and NR^(k)—C(═O); R1 is monocyclic or bicyclic heteroarylincluding from 5-10 ring atoms, optionally substituted with from 1-3R^(o); wherein from 1-4 of the ring atoms are a heteroatom independentlyselected from O, N, N—H, N—R^(o), and S; R^(o) is independently selectedfrom the group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 74. The compound or salt according toany one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is monocyclic or bicyclicheteroaryl including from 5-10 ring atoms, optionally substituted withfrom 1-3 R^(o); wherein from 1-4 of the ring atoms are a heteroatomindependently selected from O, N, N—H, N—R^(o), and S; R^(o) isindependently selected from the group consisting of: halogen; C1-C6alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; andSO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 75.The compound or salt according to any one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond; R1 ismonocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N—R^(o),and S; R^(o) is independently selected from the group consisting of:halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—;cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen.
 76. The compound or salt according to any one of claims 1-63,wherein: X is —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, andeach occurrence of R^(a) and R^(b) is independently selected from H, F,OH, C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; R1 ismonocyclic or bicyclic heteroaryl including from 5-10 ring atoms,optionally substituted with from 1-3 R^(o); wherein from 1-4 of the ringatoms are a heteroatom independently selected from O, N, N—H, N−R^(o),and S; R^(o) is independently selected from the group consisting of:halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl;C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—;cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and(i) each of R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 isfluoro; or (iii) R2 is a substituent other than hydrogen, and R3 ishydrogen.
 77. The compound or salt according to any one of claims 1-63,wherein: X is: (i) —Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; (ii) directbond; or (iii) C═O, C(R^(j))₂—C(═O), C(═O)—C(R^(j))₂, SO₂—NR^(k),NR^(k)—SO₂, C(═O)NR^(k) and NR^(k)—C(═O); R1 is C6-C10 aryl, optionallysubstituted with from 1-3 R^(o); R^(o) is independently selected fromthe group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 78. The compound or salt according toany one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is C6-C10 aryl, optionallysubstituted with from 1-3 R^(o); R^(o) is independently selected fromthe group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 79. The compound or salt according toany one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—; R1 is C6-C10 aryl, optionallysubstituted with from 1-3 R^(o); R^(o) is independently selected fromthe group consisting of: halogen; C1-C6 alkyl; fluoro(C1-C6)alkyl;hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy; fluoro(C1-C6)alkoxy; (C1-C6alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; and SO₂—(C1-C6)alkyl; R4 is hydrogenor halo; R5 is hydrogen; and (i) each of R2 and R3 is hydrogen; or (ii)R2 is hydrogen, and R3 is fluoro; or (iii) R2 is a substituent otherthan hydrogen, and R3 is hydrogen.
 80. The compound or salt according toany one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, and Y is a bond; R1 is C6-C10aryl, optionally substituted with from 1-3 R^(o); R^(o) is independentlyselected from the group consisting of: halogen; C1-C6 alkyl;fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; andSO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 81.The compound or salt according to any one of claims 1-63, wherein: X is—Y—[C(R^(a))₂]_(a)-A-[C(R^(b))₂]_(b)—B—, Y is a bond, and eachoccurrence of R^(a) and R^(b) is independently selected from H, F, OH,C1-C6 alkyl, C3-C6 cycloalkyl, NH₂, OCO—(C1-C6 alkyl), OCO—(C3-C6cycloalkyl), C1-C6 alkoxy, C1-C6 fluoroalkoxy, and cyano; R1 is C6-C10aryl, optionally substituted with from 1-3 R^(o); R^(o) is independentlyselected from the group consisting of: halogen; C1-C6 alkyl;fluoro(C1-C6)alkyl; hydroxyl; hydroxy(C₁-C₄)alkyl; C1-C6 alkoxy;fluoro(C1-C6)alkoxy; (C1-C6 alkyl)NH—; (C1-C6 alkyl)₂N—; cyano; andSO₂—(C1-C6)alkyl; R4 is hydrogen or halo; R5 is hydrogen; and (i) eachof R2 and R3 is hydrogen; or (ii) R2 is hydrogen, and R3 is fluoro; or(iii) R2 is a substituent other than hydrogen, and R3 is hydrogen. 82.The compound or salt according to any one of claims 64-81, wherein thecompound or salt has formula (Ia):


83. The compound or salt according to any one of claims 64-81, whereinthe compound or salt has formula (Ib):


84. The compound or salt according to any one of claims 64-82, wherein Ais a bond.
 85. The compound or salt according to any one of claims64-84, wherein each occurrence of R^(a) and R^(b) is independentlyselected from H, F, C1-C6 alkyl, and C3-C6 cycloalkyl.
 86. The compoundor salt according to any one of any one of claims 64-85, wherein eachoccurrence of R^(a) and R^(b) is H.
 87. The compound or salt accordingto any one of claims 64-86, wherein a is
 1. 88. The compound or saltaccording to any one of claims 64-87, wherein b is
 0. 89. The compoundor salt according to any one of claims 64-88, wherein X is CH₂.
 90. Thecompound or salt according to any one of claims 64-87 and 89, wherein bis 1, 2, or
 3. 91. The compound or salt according to any one of claims64-88 and 90, wherein X is (CH₂)₂₋₄.
 92. The compound or salt accordingto any one of claims 64-72 and 82-91, wherein R1 is C3-C10 cycloalkyl,optionally substituted with from 1-3 R^(o).
 93. The compound or saltaccording to claim 92, wherein R1 is C3-C6 cycloalkyl, optionallysubstituted with from 1-3 R^(o).
 94. The compound or salt according toclaim 93, wherein R1 is cyclopropyl, optionally substituted with from1-3 R^(o).
 95. The compound or salt according to claim 93, wherein R1 isunsubstituted C3-C6 cycloalkyl.
 96. The compound or salt according toclaim 95, wherein R1 is unsubstituted cyclopropyl.
 97. The compound orsalt according to any one of claims 1-96, wherein the compound isselected from the compounds delineated in Table
 1. 98. The compound orsalt according to claim 97, wherein the compound is selected fromA1-A16.
 99. The compound or salt according to claim 97, wherein thecompound is selected from A6-A8, A10, and A12.
 100. The compound or saltaccording to claim 97, wherein the compound is selected from A1, A4-A8,and A13-A15.
 101. The compound or salt according to claim 97, whereinthe compound is selected from A2, A3, A9, and A10.
 102. The compound orsalt according to any one of claims 1-96, wherein —X—R₁ is CH₂phenyl,optionally substituted with one or more substituents selected from haloand methyl.
 103. The compound or salt according to any one of claims1-96, wherein —XR₁ is CH₂pyridyl, optionally substituted with one ormore substituents selected from halo and methyl.
 104. The compound orsalt according to any one of claims 1-96, wherein —XR₁ is CH₂cycloalkyl,and the cycloalkyl is selected from cyclopropyl, cyclopentyl, andcyclohexyl, and is optionally substituted with one or more ofC1-C3alkyl, C1-C3alkoxy, and halo.
 105. The compound or salt accordingto claim 104, wherein —XR₁ is CH₂cyclopropyl, optionally substitutedwith one or more of C1-C3alkyl, C1-C3alkoxy, and halo.
 106. The compoundor salt according to any one of claims 1-96, wherein —X₁ isCH₂pyrazolyl, optionally substituted with one or more substituentsselected from methyl and halo.
 107. The compound or salt according toany one of claims 1-106, wherein R₂ and R₃ are each hydrogen.
 108. Thecompound or salt according to any one of claims 1-106, wherein R₂ ishydrogen and R₃ is F or Cl.
 109. The compound or salt according to anyone of claims 1-108, wherein R₄ is hydrogen.
 110. A pharmaceuticalcomposition comprising a compound, or pharmaceutically acceptable saltthereof, as claimed in any one of claims 1-109 and a pharmaceuticallyacceptable carrier.
 111. A method of inhibiting HDAC3, the methodcomprising contacting a cell with an effective amount of a compound, orpharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, or a composition according to claim
 110. 112. The methodof claim 111, wherein the compound or composition selectively inhibitsHDAC3.
 113. A method of inhibiting HDAC1 or HDAC2, the method comprisingcontacting a cell with an effective amount of a compound, orpharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, or a composition according to claim
 110. 114. The methodof claim 113, wherein the compound or composition selectively inhibitsHDAC1 or HDAC2.
 115. A method of inhibiting HDAC1, HDAC2, and HDAC3, themethod comprising contacting a cell with an effective amount of acompound, or pharmaceutically acceptable salt thereof, as claimed in anyone of claims 1-109, or a composition according to claim
 110. 116. Amethod of treating a disease or disorder mediated by HDAC1 or HDAC2 in asubject in need thereof, the method comprising administering a compound,or pharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, or a composition according to claim 110 to said subject.117. A method of treating a disease or disorder mediated by HDAC3 in asubject in need thereof, the method comprising administering a compound,or pharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, or a composition according to claim 110 to said subject.118. A method of treating a disease or disorder mediated by HDAC1,HDAC2, and HDAC3 in a subject in need thereof, the method comprisingadministering a compound, or pharmaceutically acceptable salt thereof,as claimed in any one of claims 1-109, or a composition according toclaim 110 to said subject.
 119. A method of treating a neurologicaldisorder selected from Friedreich's ataxia, myotonic dystrophy, spinalmuscular atrophy, fragile X syndrome, Huntington's disease,spinocerebellar ataxia, Kennedy's disease, amyotrophic lateralsclerosis, Niemann Pick, Pitt Hopkins, spinal and bulbar muscularatrophy, Alzheimer' s disease; a cancer; an inflammatory disease; amemory impairment condition; and a drug addiction in a patient in needthereof, the method comprising administering a compound, orpharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, or a composition according to claim 110 to said patient.120. The method of claim 119, wherein the disorder is Friedreich'sataxia.
 121. The method of claim 119, wherein the disorder isHuntington's disease.
 122. A compound, or pharmaceutically acceptablesalt thereof, as claimed in any one of claims 1-109, for use in thepreparation of a medicament.
 123. A compound, or pharmaceuticallyacceptable salt thereof, as claimed in any one of claims 1-109, for thetreatment of a disease or disorder mediated by HDAC1 or HDAC2, a diseaseor disorder mediated by HDAC3, or a neurological disorder selected fromFriedreich's ataxia, myotonic dystrophy, spinal muscular atrophy,fragile X syndrome, Huntington's disease, spinocerebellar ataxia,Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbarmuscular atrophy, Alzheimer's disease; an infection including microbialor viral infection; a cancer; an inflammatory disease; a memoryimpairment condition and a drug addiction.
 124. Use of a compound, orpharmaceutically acceptable salt thereof, as claimed in any one ofclaims 1-109, in the preparation of a medicament for the treatment orprevention of a disease or disorder mediated by HDAC1 or HDAC2, adisease or disorder mediated by HDAC3, or a neurological disorderselected from Friedreich's ataxia, myotonic dystrophy, spinal muscularatrophy, fragile X syndrome, Huntington's disease, a spinocerebellarataxia, Kennedy's disease, amyotrophic lateral sclerosis, Niemann Pick,Pitt Hopkins, spinal and bulbar muscular atrophy, Alzheimer's disease; acancer; an inflammatory disease; a memory impairment condition and adrug addiction.